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| Fetal anomalies v1.252 | SERPINA11 |
Ain Roesley gene: SERPINA11 was added gene: SERPINA11 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINA11 were set to 38831697 Phenotypes for gene: SERPINA11 were set to pericardial effusion; pleural effusion Review for gene: SERPINA11 was set to RED gene: SERPINA11 was marked as current diagnostic Added comment: 1 family with 2 fetuses. 1st fetus presented with isolated pericardial effusion and a TOP was opted. post mortem: mild subcutaneous edema with subtle facial dysmorphic features small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces 2nd fetus also presented with pleural and pericardial effusion and a TOP was opted post mortem findings were similar to fetus#1 homozygous nonsense variant in SERPINA11 was found p.(Tyr224*) Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium Sources: Literature |
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| Fetal anomalies v1.114 | RAB34 |
Sarah Pantaleo gene: RAB34 was added gene: RAB34 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAB34 were set to PMID: 37384395 Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies Penetrance for gene: RAB34 were set to Complete Review for gene: RAB34 was set to GREEN Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS. Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher). Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects. RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function. Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands. In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth. All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities. All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance. Sources: Literature |
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| Fetal anomalies v1.54 | ZMYND8 |
Zornitza Stark gene: ZMYND8 was added gene: ZMYND8 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMYND8 were set to 35916866; 32530565 Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures Review for gene: ZMYND8 was set to GREEN Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565). Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11). As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression. The protein is broadly expressed in brain and shows highest expression in early development. Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain). Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning. Sources: Expert Review |
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| Fetal anomalies v0.4729 | OXR1 |
Krithika Murali gene: OXR1 was added gene: OXR1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OXR1 were set to PMID: 31785787 Phenotypes for gene: OXR1 were set to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay - MIM#213000 Review for gene: OXR1 was set to GREEN Added comment: Early-onset condition associated with cerebellar atrophy and severe global developmental delay. Limited antenatal information provided but affected individuals were much older at the time of formal diagnosis PMID: 31785787, antenatal detection may be possible. --- 5 individuals from 3 unrelated families reported with bi-allelic variants in this gene. Presentation was in early childhood with hypotonia, global developmental delay, delayed walking at about age 3 years, and severely impaired intellectual development with profound speech delay or even absent language. All also developed epilepsy between 7 and 10 years of age, but the seizures were controlled by medication in most. Subtle nonspecific dysmorphic features included poor overall growth, large forehead, tall face, mild hypertelorism, joint hyperlaxity, and long fingers and toes. Brain imaging in all 5 individuals showed cerebellar atrophy and dysplasia. Additional cerebellar features, such as tremor, ataxia, and nystagmus, were not noted in these individuals. Sources: Literature |
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| Fetal anomalies v0.4513 | PRKD1 |
Zornitza Stark edited their review of gene: PRKD1: Added comment: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.' PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; Changed publications: 27479907, 32817298; Changed phenotypes: Congenital heart defects and ectodermal dysplasia, MIM#617364; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Fetal anomalies v0.4491 | RAPSN | Zornitza Stark Phenotypes for gene: RAPSN were changed from FETAL AKINESIA DEFORMATION SEQUENCE; CONGENITAL MYASTHENIC SYNDROME WITH ACETYLCHOLINE RECEPTOR DEFICIENCY to Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency, MIM#616326; Fetal akinesia deformation sequence 2, MIM# 618388 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4490 | RAPSN | Zornitza Stark edited their review of gene: RAPSN: Changed phenotypes: Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency, MIM#616326, Fetal akinesia deformation sequence 2, MIM# 618388 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4372 | SLC35D1 | Zornitza Stark Phenotypes for gene: SLC35D1 were changed from SCHNECKENBECKEN DYSPLASIA to Schneckenbecken dysplasia 269250, MONDO:0010013; O-xylosyl/N-acetylgalactosaminylglycan synthesis deficiencies (Disorders of protein O-glycosylation) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4253 | SYT2 |
Belinda Chong gene: SYT2 was added gene: SYT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SYT2 were set to 25192047; 32776697; 32250532; 30533528 Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461 Review for gene: SYT2 was set to GREEN gene: SYT2 was marked as current diagnostic Added comment: Myasthenic syndrome bi-allelic #619461- Decreased fetal movements Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. Sources: Literature |
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| Fetal anomalies v0.3934 | SLC37A4 |
Zornitza Stark changed review comment from: Bi-allelic LOF variants in this gene cause glycogen storage disorder. Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease. Sources: Literature; to: Bi-allelic LOF variants in this gene cause glycogen storage disorder. Clinical presentation is typically post-natal. Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease. Sources: Literature |
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| Fetal anomalies v0.3908 | PLOD3 |
Krithika Murali gene: PLOD3 was added gene: PLOD3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLOD3 were set to 30237576; 18834968 Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency - MIM#612394 Review for gene: PLOD3 was set to GREEN Added comment: 4 unrelated families reported with biallelic PLOD3 variants and Stickler-syndrome like phenotype including antenatal phenotype of IUGR in one family. -- PMID 30237576 Maddirevula et al 2019 - report homozygous nonsense variant in a proband with dysmorphic facies, microcephaly, ptosis and contractures. No antenatal information provided. PMID 31129566 Ewans et al 2019 - report 3 affected siblings with a Stickler-syndrome like disorder. - Patient 1 had congenital nystagmus and presented with hearing loss and myopia. On examination aged 2, noted to have dysmorphic features - prominent eyes, hypertelorism, malar hypoplasia, an upturned nose, low-set ears and microretrognathia. - Patient 2 noted to have camptodactyly and clinodactyly postnatally. On examination age 5 noted to have DIP joint contractures and mild skin syndactyly. - Patient 3 - breech delivery. bilateral hand foot camptodactyly, facial dysmorphism. - No antenatal features reported. PMID 30463024 Vahidnehzad et al 2019 - report a male proband from a consanguineous Iranian Baloch family referred for assessment age 4.5. Noted to have developmental delay, musculoskeletal manifestations including scoliosis, flexion contractions, cutaneous syndactyly, right diaphragmatic eventration, ocular anomalies, growth failure and skin blisters. No concerns antenatally. Postnatally noted to have cataract and facial dysmorphism (midface hypoplasia). Homozygous PLOD3 missense variant identified, parents unaffected carriers. PLOD3 mRNA levels in the patient’s fibroblasts measured by whole-transcriptome sequencing and confirmed by RT-PCR, were the same as in control cells, however, the expression of type VII collagen was reduced significantly. No antenatal features reported. PMID: 18834968 Salo et al 2008 - a female proband with significant IUGR, characteristic craniofacial profile, diaphragm eventration, skeletal anomalies (bilateral talipes equinovarus, flexion contractures, scoliosis from age 7), skin anomalies incl blistering and ocular anomalies. One 28 week male stillborn sibling noted to have significant IUGR and skeletal anomalies on post-mortem. Supportive functional evidence. Compound het PLOD3 variants. Sources: Literature |
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| Fetal anomalies v0.3692 | HACE1 | Zornitza Stark Marked gene: HACE1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3692 | HACE1 | Zornitza Stark Gene: hace1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3692 | HACE1 | Zornitza Stark Phenotypes for gene: HACE1 were changed from HACE1 related disorder to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; MONDO:0014764 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3691 | HACE1 | Zornitza Stark Publications for gene: HACE1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3690 | HACE1 | Zornitza Stark Classified gene: HACE1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3690 | HACE1 | Zornitza Stark Gene: hace1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3689 | HACE1 | Zornitza Stark edited their review of gene: HACE1: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3610 | ST3GAL5 |
Zornitza Stark changed review comment from: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported.; to: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.3464 | HOXB6 |
Krithika Murali gene: HOXB6 was added gene: HOXB6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HOXB6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HOXB6 were set to 17003840; 22371315 Phenotypes for gene: HOXB6 were set to Hypospadias Review for gene: HOXB6 was set to RED Added comment: PMID 17003840 Chen et al 2007 report 2 babies with hypospadias and heterozygous HOXB6 variants. Cohort of 90 unrelated Chinese patients with hypospadias and 380 controls. x1 patient - heterozygous, maternally inherited HOXB6 c.124C>A p.P42T in a child with scrotal, micropenis, bifid scrotum, cryptorchidism. Baby also has maternally inherited SRD5A2 and de novo MID1 variant. The HOXB6 variant is absent from gnomad v2, v3, not previously reported in ClinVar, minor GS change (38), moderately conserved (change in non-placental mammals), not in a region of missense constraint. x1 patient - penile hypospadias, heterozygous HOXB6 c.367T>C p.C123R. No segregation information. 5 hets (East Asian, gnomad v2), 2 hets (East Asian, gnomad v3). GS 180, conserved in mammals (changed in birds), not in a region of missense constraint, not previously reported in ClinVar, predicted to escape NMD. x2 patients with hypospadias from a single study, variants of uncertain significance. Sources: Literature |
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| Fetal anomalies v0.3295 | IRX5 | Zornitza Stark Phenotypes for gene: IRX5 were changed from HYPERTELORISM, SEVERE, WITH MIDFACE PROMINENCE, MYOPIA, MENTAL RETARDATION, AND BONE FRAGILITY to Hamamy syndrome, MIM# 611174 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3140 | COL9A3 |
Krithika Murali gene: COL9A3 was added gene: COL9A3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COL9A3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: COL9A3 were set to 33570243; 31090205; 30450842; 25381065; 24273071; 15551337 Phenotypes for gene: COL9A3 were set to Epiphyseal dysplasia, multiple, 3, with or without myopathy - MIM#600969; Stickler syndrome Review for gene: COL9A3 was set to GREEN Added comment: 6 patients from 4 families reported with biallelic variants associated with a Stickler syndrome like phenotype. All of these cases characterised by the absence of cleft palate, which is noted more commonly in other autosomal dominant forms of Stickler syndrome. Potential antenatally detectable features described with biallelic COL9A3 variants include fetal growth restriction (1/6), midface hypoplasia (6/6), tibial and femoral bowing (1/6) PMID 33570243 Markova et al 2021 - report a patient with novel Class 4 compound heterozygous COL9A3 variants confirmed to be in trans. Antenatal USS identified fetal growth restriction in the third trimester. Examination findings by clinical geneticist aged 2 provided, including dysmorphic facial features noted - slightly flattened nasal bridge, small nose, mild mid-facial hypoplasia, high palate. PMID 31090205 – Nixon et al 2019 - homozygous COL9A3 variant identified in proband, consanguineous family. Antenatal phenotype not provided, mid-facial hypoplasia noted. PMID: 30450842 – Hanson-Kahn et al 2018 - proband homozygous for LoF COL9A3 variants. Phenotypic features included moderate to severe sensorineural hearing loss, high myopia, mid-face hypoplasia and both tibial and femoral bowing at birth. PMID 24273071 Faletra et al 2014 - first reported family with AR COL9A3 associated Stickler syndrome due to homozygous LoF variants. 3 siblings with hearing loss, midface hypoplasia, high myopia, variable severity ID from consanguineous Moroccan family. -- Variants in COL9A3 have previously been associated with autosomal dominant multiple epiphyseal dysplasia, susceptibility to an intervertebral disc disease, and hearing loss. Generally milder phenotype than individuals with biallelic variants. However, PMID 33633367 Nash et al 2021 - report 2 families with heterozygous COL9A3 variants with a more severe Stickler-like phenotype including severe peripheral lattice vitreoretinal abnormalities and mild/moderate sensorineural hearing loss in some cases. No antenatal information provided Sources: Literature |
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| Fetal anomalies v0.3123 | POP1 |
Zornitza Stark changed review comment from: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability.; to: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability. At least 4 unrelated families reported. |
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| Fetal anomalies v0.3123 | POP1 | Zornitza Stark changed review comment from: Primarily a skeletal dysplasia, mild LD described in some but overall I don't think this is the right panel.; to: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3006 | PGM3 |
Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally. However, more severe presentations with skeletal abnormalities and congenital malformations reported in PMID 28543917 and 24931394. |
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| Fetal anomalies v0.3003 | PGM3 |
Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally. |
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| Fetal anomalies v0.2950 | MUSK | Alison Yeung Phenotypes for gene: MUSK were changed from Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency; Fetal akinesia deformation sequence to Fetal akinesia deformation sequence 1, MIM# 208150; MONDO:0100101 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2728 | SHMT2 |
Krithika Murali gene: SHMT2 was added gene: SHMT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Polymicrogyria; corpus callosum anomalies; Microcephaly; Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities - #619121 Review for gene: SHMT2 was set to GREEN Added comment: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities particularly thin corpus callosum and polymicrogyria (NEDCASB) associated with biallelic SHMT2 variants. Antenatal detection of microcephaly reported. -- Detailed PanelApp review Oct 2020 - no new evidence to add García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs. Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones. SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes. While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect. The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity). Sources: Literature |
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| Fetal anomalies v0.2728 | GAMT | Zornitza Stark Phenotypes for gene: GAMT were changed from GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY to Cerebral creatine deficiency syndrome 2 MIM#612736 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2727 | NMNAT2 | Zornitza Stark Phenotypes for gene: NMNAT2 were changed from hydropic placenta; hydrocephalus; micrognathia; bilateral hypoplastic lungs; hypoplastic cerebellum; severely reduced skeletal muscle mass or absence; cleft palate; hydrops fetalis; flexion contractures of all extremities; cystic hygroma to Hydrops fetalis and multiple fetal anomalies; polyneuropathy; erythromelalgia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2665 | WNT5A | Zornitza Stark changed review comment from: LD/ID reported in ~20% according to this cohort/literature review.; to: Robinow syndrome is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1965 | KCTD7 | Zornitza Stark Phenotypes for gene: KCTD7 were changed from PROGRESSIVE MYOCLONIC EPILEPSY TYPE 3; NEURONAL CEROID LIPOFUSCINOSIS to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1933 | KCTD7 | Daniel Flanagan reviewed gene: KCTD7: Rating: RED; Mode of pathogenicity: None; Publications: 33767931, 33970744, 22693283, 22748208; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1671 | SETBP1 | Zornitza Stark Phenotypes for gene: SETBP1 were changed from DEVELOPMENTAL AND EXPRESSIVE LANGUAGE DELAY, MIM#616078; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME, MIM#269150 to Schinzel-Giedion midface retraction syndrome, MIM# 269150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1669 | SETBP1 | Zornitza Stark reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Schinzel-Giedion midface retraction syndrome, MIM# 269150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1662 | SETBP1 | Seb Lunke Phenotypes for gene: SETBP1 were changed from DEVELOPMENTAL AND EXPRESSIVE LANGUAGE DELAY; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME to DEVELOPMENTAL AND EXPRESSIVE LANGUAGE DELAY, MIM#616078; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME, MIM#269150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1633 | ACAT1 | Zornitza Stark Phenotypes for gene: ACAT1 were changed from ALPHA-METHYLACETOACETIC ACIDURIA to Alpha-methylacetoacetic aciduria, MIM# 203750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1469 | HSPA9 |
Krithika Murali gene: HSPA9 was added gene: HSPA9 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: HSPA9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: HSPA9 were set to 26598328; 32869452; 26491070 Phenotypes for gene: HSPA9 were set to Even-plus syndrome - MIM#616854; Anemia, sideroblastic, 4- #182170 Review for gene: HSPA9 was set to GREEN Added comment: Biallelic variants in 4 individuals from 5 families. Significant skeletal features and marked nasal hypoplasia with mid-face hypoplasia. 2/5 with developmental delay and abnormalities of the corpus callosum 4/5 with congenital heart disease Biallelic variants also associated with congenital sideroblastic anaemia. Some patients with a a heterozygous LoF variant have developed congenital sideroblastic anaemia if a particular SNP is presence in trans correlating with reduced mRNA expression (pseudodominant pattern of inheritance) Sources: Literature, Expert list |
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| Fetal anomalies v0.1423 | CTNND1 |
Zornitza Stark changed review comment from: 4 individuals from 3 unrelated families with blepharocheilodontic syndrome and mutations in the CTNND1 gene reported originally in PMID 28301459. All had eyelid anomalies, including ectropion of the lower lids, euryblepharon, lagophthalmia, and distichiasis. In addition, all 4 showed typical facial dysmorphism with hypertelorism, flat face, and high forehead, and all had conical teeth and tooth agenesis. Three had cleft lip and palate, 3 had hair anomalies, and 1 had hypothyroidism due to hypoplasia or aplasia of the thyroid gland. None of the patients exhibited anal atresia or neural tube defects. PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). This more recent publication suggests a broader phenotype associated with CTNND1 variants including dev delay, ADHD/ASD, behavioural issues. Unclear from description whether significant ID present. Sources: Literature; to: 4 individuals from 3 unrelated families with blepharocheilodontic syndrome and mutations in the CTNND1 gene reported originally in PMID 28301459. All had eyelid anomalies, including ectropion of the lower lids, euryblepharon, lagophthalmia, and distichiasis. In addition, all 4 showed typical facial dysmorphism with hypertelorism, flat face, and high forehead, and all had conical teeth and tooth agenesis. Three had cleft lip and palate, 3 had hair anomalies, and 1 had hypothyroidism due to hypoplasia or aplasia of the thyroid gland. None of the patients exhibited anal atresia or neural tube defects. PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). This more recent publication suggests a broader phenotype associated with CTNND1 variants including dev delay, ADHD/ASD, behavioural issues. Sources: Literature |
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| Fetal anomalies v0.1226 | CHRNB1 | Zornitza Stark Phenotypes for gene: CHRNB1 were changed from ?Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency, 616314; Myasthenic syndrome, congenital, 2A, slow-channel, 616313 to Myasthenic syndrome, slow-channel congenital, 601462 Myasthenic syndrome, congenital, 2A, slow-channel, 616313; Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency, 616314 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1223 | CHRNB1 | Zornitza Stark reviewed gene: CHRNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8872460, 8651643, 27375219, 32504635, 10562302; Phenotypes: Myasthenic syndrome, slow-channel congenital, 601462 Myasthenic syndrome, congenital, 2A, slow-channel, 616313, Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency, 616314; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1081 | DYM |
Zornitza Stark changed review comment from: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported.; to: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported. Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest, features identical to those of Dyggve-Melchior-Clausen disease. The two conditions likely represent a spectrum rather than two distinct disorders. |
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| Fetal anomalies v0.1081 | DYM | Zornitza Stark changed review comment from: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests; to: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1081 | DYM | Zornitza Stark commented on gene: DYM: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.998 | NALCN | Seb Lunke Phenotypes for gene: NALCN were changed from HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES; CONGENITAL CONTRACTURES OF THE LIMBS AND FACE, HYPOTONIA, AND DEVELOPMENTAL DELAY; SEVERE HYPOTONIA, SPEECH IMPAIRMENT, AND COGNITIVE DELAY to Congenital contractures of the limbs and face, hypotonia, and developmental delay (MIM#616266); Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.990 | NAGA | Seb Lunke Phenotypes for gene: NAGA were changed from SCHINDLER DISEASE; KANZAKI DISEASE to Kanzaki disease (MIM# 609242); Schindler disease, type I and type II (MIM#609241); alpha-N-acetylgalactosaminidase deficiency (MONDO:0017779) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.957 | NFIX |
Daniel Flanagan changed review comment from: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. Atrial septal defect; to: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. |
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| Fetal anomalies v0.957 | NALCN | Daniel Flanagan reviewed gene: NALCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 25683120, 23749988, 24075186; Phenotypes: Congenital contractures of the limbs and face, hypotonia, and developmental delay (MIM#616266), Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.957 | NAGA | Daniel Flanagan reviewed gene: NAGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11313741, 31468281, 15619430, 8782044; Phenotypes: Kanzaki disease (MIM# 609242), Schindler disease, type I and type II (MIM#609241), alpha-N-acetylgalactosaminidase deficiency (MONDO:0017779); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.886 | ATP11A |
Krithika Murali gene: ATP11A was added gene: ATP11A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP11A were set to 34403372 Phenotypes for gene: ATP11A were set to Ventriculomegaly; cerebral atrophy; hypoplasia corpus callosum Review for gene: ATP11A was set to AMBER Added comment: PMID: 34403372 - Single de novo missense variant reported in a patient with developmental delay and neurological deterioration. Epilepsy diagnosed at 2 weeks of age followed by global developmental delay, mild hypothyroidism and cataracts. - Repeated MRI (earliest published is from age 2 yo) showed non-progressive severe cerebral atrophy, enlarged subarachnoid space, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. - Axonal neuropathy suggested. - K/I heterozygous mice died perinatally. - Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc. gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets. Sources: Literature |
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| Fetal anomalies v0.886 | MMP9 |
Krithika Murali gene: MMP9 was added gene: MMP9 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MMP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMP9 were set to 19615667; 28342220; 34407464 Phenotypes for gene: MMP9 were set to Metaphyseal anadysplasia 2 - MIM# 613073 Review for gene: MMP9 was set to GREEN Added comment: Biallelic variants in MMP9 associated with autosomal recessive, metaphyseal anadysplasia type 2. Usually associated with a milder phenotype characterised by normal birth length, transitory bowing of the legs, spontaneous regression and disappearance of metaphyseal alterations during adolescence. Phenotype of MAD type 2 cases secondary to biallelic MMP13 gene mutations (more reported cases associated with this gene) similar to MMP9 associated cases. MMP9-associated MAD type 2 cases reported so far: x2 sibs from 1 consanguineous Pakistani family diagnosed postnatally with normal stature, genu varum, metaphyseal fraying during infancy (PMID 19615667) x1 child from consanguineous family with homozygous nonsense variants diagnosed age 19 months with improvement of skeletal manifestations over a short period and by an early age (PMID 34407464) x2 siblings from x1 non-consanguineous Jewish Caucasian family reported with more severe phenotype than other previously reported cases for MAD type 2 (PMID 28342220). Both siblings diagnosed during 2nd trimester with shortening of long bones. x1 fetus terminated at 19 weeks gestation - dysmorphic face including micrognathia, flattened nose, hypertelorism, short neck and hypoplastic lungs. 2nd liveborn female - reduced body length at birth (-4 SD), facial dysmorphism, cleft palate, anteriorly placed anus and other anomalies. No radiographic metaphyseal anomalies. Both children identified as having the same homozygous MMP9 missense variants. Authors acknowledge the phenotype is more severe than other previously reported cases of MAD type 2 associated with MMP9 or MMP13 gene variants. Some dispute regarding this prenatal case as detailed by PMID 34407464 such as possibility of an alternative skeletal dysplasia diagnosis (Desbuquois dypslasia type 2) and presence of 5 homozygotes in gnomad with the same missense variants - ?founder mutation. Borderline amber-green gene in the prenatal setting based on current evidence. Sources: Expert list, Literature |
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| Fetal anomalies v0.842 | AMMECR1 | Zornitza Stark reviewed gene: AMMECR1: Rating: RED; Mode of pathogenicity: None; Publications: 27811305, 28089922, 29193635; Phenotypes: Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis, MIM# 300990; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.841 | AMACR | Zornitza Stark Phenotypes for gene: AMACR were changed from Alpha-methylacyl-CoA racemase deficiency, 614307 to Bile acid synthesis defect, congenital, 4, MIM# 214950 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.826 | ALG11 |
Zornitza Stark changed review comment from: Usually transferrin isoforms abnormal, however normal patterns have been reported in this condition. Abnormalities in fibroblasts accumulation of a N2M3 and N2M4 (N=N-acetylglucosamine, M=Mannose) LLO glycans Hypoglycosylation of GP130. Principal phenotypic features include: Developmental disability; Epilepsy; Dysmorphic features; Microcephaly; Hypotonia; Hypertonia, Hyperreflexia; Sensorineural deafness; Eye/Visual Problems; Feeding problems; to: Usually transferrin isoforms abnormal, however normal patterns have been reported in this condition. Abnormalities in fibroblasts accumulation of a N2M3 and N2M4 (N=N-acetylglucosamine, M=Mannose) LLO glycans Hypoglycosylation of GP130. Principal phenotypic features include: Developmental disability; Epilepsy; Dysmorphic features; Microcephaly; Hypotonia; Hypertonia, Hyperreflexia; Sensorineural deafness; Eye/Visual Problems; Feeding problems Onset is in first year of life, microcephaly rarely reported. |
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| Fetal anomalies v0.774 | ACSL4 | Zornitza Stark Phenotypes for gene: ACSL4 were changed from ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS; MENTAL RETARDATION X-LINKED TYPE 63 to Mental retardation, X-linked 63 , MIM#300387 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.610 | CRLF1 |
Zornitza Stark edited their review of gene: CRLF1: Added comment: Micrognathia, camptodactyly are features. Crisponi/cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis. Multiple unrelated families reported.; Changed rating: GREEN; Changed publications: 12509788, 17436251, 17436252 |
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| Fetal anomalies v0.587 | MMP13 |
Daniel Flanagan changed review comment from: At least 7 families described with either mono or biallelic variants reports. Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13.; to: At least 7 families described with either mono (Metaphyseal anadysplasia) or biallelic (Metaphyseal dysplasia, Spahr type) variants reports. Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13. |
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| Fetal anomalies v0.197 | ASXL1 | Zornitza Stark changed review comment from: Colobomas reported.; to: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound ID, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints -- many of these features would be identifiable antenatally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.31 | ACE | Zornitza Stark Marked gene: ACE as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.31 | ACE | Zornitza Stark Gene: ace has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.31 | ACE | Zornitza Stark Phenotypes for gene: ACE were changed from Renal tubular dysgenesis 267430 to Renal tubular dysgenesis, MIM# 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.30 | ACE | Zornitza Stark Publications for gene: ACE were set to 30058238 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.29 | ACE | Zornitza Stark reviewed gene: ACE: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM# 267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.0 | NAGS |
Zornitza Stark gene: NAGS was added gene: NAGS was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: NAGS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NAGS were set to N-ACETYLGLUTAMATE SYNTHASE DEFICIENCY |
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| Fetal anomalies v0.0 | HACE1 |
Zornitza Stark gene: HACE1 was added gene: HACE1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: HACE1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HACE1 were set to HACE1 related disorder |
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| Fetal anomalies v0.0 | GAMT |
Zornitza Stark gene: GAMT was added gene: GAMT was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: GAMT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GAMT were set to GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY |
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| Fetal anomalies v0.0 | ACAT1 |
Zornitza Stark gene: ACAT1 was added gene: ACAT1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: ACAT1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACAT1 were set to ALPHA-METHYLACETOACETIC ACIDURIA |
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| Fetal anomalies v0.0 | NMNAT2 |
Zornitza Stark gene: NMNAT2 was added gene: NMNAT2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NMNAT2 were set to 31132363; 23082226; 31136762 Phenotypes for gene: NMNAT2 were set to hydropic placenta; hydrocephalus; micrognathia; bilateral hypoplastic lungs; hypoplastic cerebellum; severely reduced skeletal muscle mass or absence; cleft palate; hydrops fetalis; flexion contractures of all extremities; cystic hygroma |
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| Fetal anomalies v0.0 | IRX5 |
Zornitza Stark gene: IRX5 was added gene: IRX5 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: IRX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IRX5 were set to HYPERTELORISM, SEVERE, WITH MIDFACE PROMINENCE, MYOPIA, MENTAL RETARDATION, AND BONE FRAGILITY |
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| Fetal anomalies v0.0 | CHRNE |
Zornitza Stark gene: CHRNE was added gene: CHRNE was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CHRNE was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: CHRNE were set to Myasthenic syndrome, congenital, 4A, slow-channel, 605809; Myasthenic syndrome, congenital, 4B, fast-channel, 616324; Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency, 608931 |
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| Fetal anomalies v0.0 | CHRNB1 |
Zornitza Stark gene: CHRNB1 was added gene: CHRNB1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CHRNB1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: CHRNB1 were set to ?Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency, 616314; Myasthenic syndrome, congenital, 2A, slow-channel, 616313 |
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| Fetal anomalies v0.0 | AMMECR1 |
Zornitza Stark gene: AMMECR1 was added gene: AMMECR1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: AMMECR1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: AMMECR1 were set to Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis, 300990 |
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| Fetal anomalies v0.0 | AMACR |
Zornitza Stark gene: AMACR was added gene: AMACR was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: AMACR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AMACR were set to Alpha-methylacyl-CoA racemase deficiency, 614307 |
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| Fetal anomalies v0.0 | ACSL4 |
Zornitza Stark gene: ACSL4 was added gene: ACSL4 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: ACSL4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: ACSL4 were set to ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS; MENTAL RETARDATION X-LINKED TYPE 63 |
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| Fetal anomalies v0.0 | SETBP1 |
Zornitza Stark gene: SETBP1 was added gene: SETBP1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SETBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SETBP1 were set to DEVELOPMENTAL AND EXPRESSIVE LANGUAGE DELAY; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME |
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| Fetal anomalies v0.0 | RAPSN |
Zornitza Stark gene: RAPSN was added gene: RAPSN was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: RAPSN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RAPSN were set to FETAL AKINESIA DEFORMATION SEQUENCE; CONGENITAL MYASTHENIC SYNDROME WITH ACETYLCHOLINE RECEPTOR DEFICIENCY |
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| Fetal anomalies v0.0 | NALCN |
Zornitza Stark gene: NALCN was added gene: NALCN was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: NALCN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: NALCN were set to HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION AND CHARACTERISTIC FACIES; CONGENITAL CONTRACTURES OF THE LIMBS AND FACE, HYPOTONIA, AND DEVELOPMENTAL DELAY; SEVERE HYPOTONIA, SPEECH IMPAIRMENT, AND COGNITIVE DELAY |
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| Fetal anomalies v0.0 | MUSK |
Zornitza Stark gene: MUSK was added gene: MUSK was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: MUSK was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MUSK were set to Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency; Fetal akinesia deformation sequence |
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| Fetal anomalies v0.0 | ACE |
Zornitza Stark gene: ACE was added gene: ACE was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACE were set to 30058238 Phenotypes for gene: ACE were set to Renal tubular dysgenesis 267430 |
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