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| Fetal anomalies v1.160 | MFN2 |
Andrew Fennell gene: MFN2 was added gene: MFN2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MFN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MFN2 were set to PMID: 37804319 Phenotypes for gene: MFN2 were set to Mitochondrial disease, MONDO:0044970, MFN2-related Review for gene: MFN2 was set to AMBER Added comment: A single report of fetus with severe antenatal encephalopathy with lissencephaly, polymicrogyria, and cerebellar atrophy. The authors identified a homozygous in-frame deletion leading to exon 16 skipping and in-frame loss of 50 amino acids 13 (p.Gln574_Val624del). Functional evidence of mitochondrial dysfunction (clumping) and respiratory chain complex deficiencies. Sources: Literature |
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| Fetal anomalies v1.67 | NODAL |
Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad. The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED. A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance. Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987 |
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| Fetal anomalies v1.58 | KIF5B |
Chirag Patel gene: KIF5B was added gene: KIF5B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF5B were set to PMID: 35342932 Phenotypes for gene: KIF5B were set to Kyphomelic dysplasia, no OMIM # Review for gene: KIF5B was set to GREEN Added comment: 4 individuals with Kyphomelic dysplasia (severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. WES found de novo heterozygous missense variants in KIF5B encoding kinesin-1 heavy chain. All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. No functional studies of variants. Previously 2 animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte-specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity. Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages. Sources: Literature |
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| Fetal anomalies v0.3217 | GFPT1 |
Zornitza Stark changed review comment from: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS. The GFPT1 gene encodes an isoform of glutamine:fructose-6-phosphate amidotransferase (GFAT), which catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine 6-phosphate and glutamate. It is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway. Hexosamine is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans. Muscle samples from several patients showed decreased protein glycosylation, suggesting this is a disorder of glycosylation. However, there is also some data put forward in PMID 30635494 that this may be a mitochondrial condition.; to: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS. Presentation typically in childhood/adolescence. |
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| Fetal anomalies v0.3151 | SF3B2 |
Krithika Murali gene: SF3B2 was added gene: SF3B2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SF3B2 were set to 34344887 Phenotypes for gene: SF3B2 were set to Craniofacial microsomia Review for gene: SF3B2 was set to GREEN Added comment: No new relevant published evidence since PanelApp review Aug 2021 -- Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus resulted in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases. Sources: Literature |
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| Fetal anomalies v0.2892 | MVK |
Krithika Murali gene: MVK was added gene: MVK was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MVK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MVK were set to 27012807; 16722536 Phenotypes for gene: MVK were set to Mevalonic aciduria-#610377; Hyper-IgD syndrome - #260920 Review for gene: MVK was set to GREEN Added comment: Biallelic MVK variants associated with mevalonate kinate deficiencies - an overlapping spectrum of phenotypes includes mevalonic aciduria (MVA) on the severe end and hyper-IgD syndrome (HIDS) generally having a less severe clinical course and later diagnosis. Fetal manifestations of MVA reported include microcephaly and hydrops fetalis. Sources: Literature |
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| 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 v0.2604 | MAT1A | Zornitza Stark Phenotypes for gene: MAT1A were changed from METHIONINE ADENOSYLTRANSFERASE DEFICIENCY to Hypermethioninemia, persistent, autosomal dominant, due to methionine adenosyltransferase I/III deficiency MIM#250850; Methionine adenosyltransferase deficiency, autosomal recessive MIM#250850; Disorders of the metabolism of sulphur amino acids | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2307 | MAT1A | Ain Roesley reviewed gene: MAT1A: Rating: RED; Mode of pathogenicity: None; Publications: 27604308, 7560086; Phenotypes: Hypermethioninemia, persistent, autosomal dominant, due to methionine adenosyltransferase I/III deficiency MIM#250850, Methionine adenosyltransferase deficiency, autosomal recessive MIM#250850, Disorders of the metabolism of sulphur amino acids; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.460 | IDS | Zornitza Stark Marked gene: IDS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.460 | IDS | Zornitza Stark Gene: ids has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.460 | IDS | Zornitza Stark Phenotypes for gene: IDS were changed from MUCOPOLYSACCHARIDOSIS TYPE 2 to Mucopolysaccharidosis II MIM#309900; MONDO:0010674; Hunter syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.459 | IDS | Zornitza Stark Publications for gene: IDS were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.458 | IDS | Zornitza Stark reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis II MIM#309900, MONDO:0010674, Hunter syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.428 | IDS | Ain Roesley reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921913, 9762601, 8940265, 1901826; Phenotypes: Mucopolysaccharidosis II MIM#309900, MONDO:0010674, Hunter syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.0 | IDS |
Zornitza Stark gene: IDS was added gene: IDS was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: IDS were set to MUCOPOLYSACCHARIDOSIS TYPE 2 |
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