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| Fetal anomalies v1.234 | CNOT1 |
Zornitza Stark edited their review of gene: CNOT1: Added comment: LIMITED by ClinGen for holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787 ClinGen curation: CNOT1 was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between CNOT1 and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately.; Changed rating: AMBER; Changed phenotypes: Holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787 |
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| Fetal anomalies v1.210 | HEY2 |
Ain Roesley gene: HEY2 was added gene: HEY2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: HEY2 were set to 32820247 Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms Review for gene: HEY2 was set to RED gene: HEY2 was marked as current diagnostic Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance). Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies. Sources: Literature |
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| Fetal anomalies v0.4700 | MORC2 |
Krithika Murali gene: MORC2 was added gene: MORC2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MORC2 were set to 32693025 Phenotypes for gene: MORC2 were set to Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy - MIM#619090 Review for gene: MORC2 was set to RED Added comment: No new publications since last PanelApp review Dec 2020. No antenatal features reported. --- MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Hearing loss was observed in 11/19 subjects, primarily SNHL. Sources: Literature |
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| Fetal anomalies v0.2584 | SMS | Zornitza Stark Marked gene: SMS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2584 | SMS | Zornitza Stark Gene: sms has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2216 | SMS | Chirag Patel Classified gene: SMS as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2216 | SMS | Chirag Patel Gene: sms has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2215 | SMS | Chirag Patel changed review comment from: Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally/perinatally. Not suitable for fetal anomalies panel.; to: X-linked syndromic intellectual developmental disorder with characteristic features including dysmorphism, marfanoid habitus, unsteady gait, nasal dysarthric speech, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally. Not suitable for fetal anomalies panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2215 | SMS | Chirag Patel reviewed gene: SMS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1469 | TBX2 |
Krithika Murali gene: TBX2 was added gene: TBX2 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TBX2 were set to 29726930 Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223; Congenital heart disease; skeletal abnormalities; thymus aplasia Review for gene: TBX2 was set to GREEN Added comment: Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects (ASD, PDA, double outlet right ventricle, pulmonary stenosis), skeletal abnormalities (camptodactyly, congenital fusion thoracic spine, hemivertebrae ).Thymus aplasia/hypoplasia, cleft palate also noted. Other associated features include - facial dysmorphisms, variable developmental delay, and endocrine system disorders (e.g. autoimmune hypothyroidism, hypoparathyroidism). Sources: Literature, Expert list |
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| Fetal anomalies v0.960 | ARID2 |
Zornitza Stark changed review comment from: More than 10 unrelated individuals reported.; to: More than 10 unrelated individuals reported. Short stature and minor dysmorphisms/congenital anomalies reported, e.g. micrognathia. |
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| Fetal anomalies v0.864 | SMAD2 |
Zornitza Stark gene: SMAD2 was added gene: SMAD2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD2 were set to 29967133; 30157302; 23665959 Phenotypes for gene: SMAD2 were set to Aortic and arterial aneurysmal disease; connective tissue disease; congenital heart disease Review for gene: SMAD2 was set to GREEN Added comment: PMID: 30157302 - Two distinct phenotypes associated with pathogenic variants in SMAD2: complex congenital heart disease with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities. No genotype/phenotype correlation has been established so far. PMID: 30157302, PMID: 23665959 - 5 individuals reported with the CHD phenotype Sources: Expert Review |
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| Fetal anomalies v0.607 | CREBBP |
Zornitza Stark changed review comment from: Well established gene-disease association with RTS, deletions reasonably frequent. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported.; to: Well established gene-disease association with RTS, deletions reasonably frequent. Microcephaly is a feature. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported. |
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| Fetal anomalies v0.22 | ACTA2 |
Krithika Murali edited their review of gene: ACTA2: Added comment: Multisystemic smooth muscle dysfunction syndrome (MSMDS) presents with a recognizable pattern of complications, including congenital mydriasis, patent ductus arteriosus (PDA), pulmonary artery hypertension, aortic and other arterial aneurysms, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, and hypotonic bladder. More than 40 unrelated individuals reported, missense at p.Arg179 position.; Changed rating: GREEN; Changed publications: 20734336, 29300374; Changed phenotypes: Multisystemic smooth muscle dysfunction syndrome - MIM# 613834 |
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| Fetal anomalies v0.0 | SMS |
Zornitza Stark gene: SMS was added gene: SMS was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SMS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: SMS were set to Mental retardation, X-linked, Snyder-Robinson type, OMIM:309583; Syndromic X-linked intellectual disability Snyder type, MONDO:0010664 |
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