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| Fetal anomalies v1.315 | CTGF |
Zornitza Stark gene: CTGF was added gene: CTGF was added to Fetal anomalies. Sources: Literature new gene name tags were added to gene: CTGF. Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTGF were set to 39506047 Phenotypes for gene: CTGF were set to Kyphomelic dysplasia Review for gene: CTGF was set to AMBER Added comment: CCN2 is the new HGNC approved name. PMID: 39506047 Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia. A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state. Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent or missing tails. A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5. Sources: Literature |
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| Fetal anomalies v1.274 | GMPPA | Ain Roesley Phenotypes for gene: GMPPA were changed from Alacrima, achalasia, and mental retardation syndrome (MIM# 615510) to Alacrima, achalasia, and impaired intellectual development syndrome (MIM# 615510) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.198 | NARS | Zornitza Stark reviewed gene: NARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, MIM# 619091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.182 | WDR44 |
Andrew Fennell gene: WDR44 was added gene: WDR44 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WDR44 were set to PMID: 38191484 Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related Review for gene: WDR44 was set to GREEN Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development. WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model. The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients. Sources: Literature |
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| Fetal anomalies v1.4 | NARS |
Krithika Murali gene: NARS was added gene: NARS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NARS were set to 32738225; 32788587 Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive - MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant - MIM#619092 Review for gene: NARS was set to GREEN Added comment: HGNC approved gene symbol - NARS1 Both mono allelic and biallelic variants associated with a progressive neurological disorder with onset in infancy. Antenatal features reported. PMID 32738225 - reports roband with de novo heterozygous variant - IUGR and oligohydramnios noted prenatally. At birth noted to have low weight and OFC for gestational age. Proband with homozygous variant diagnosed with microcephaly, seizures and FTT in the neonatal period. Proband with compound het variants born with a low weight (-2.38 SD) and height (-3.76 SD) for gestational age. Review of supplementary material table - microcephaly at birth reported in 17 unrelated families. Sources: Literature |
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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 v0.4715 | C16orf62 |
Zornitza Stark changed review comment from: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251). Microphthalmia and multiple other anomalies. Sources: Expert Review; to: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impaired autophagy and VPS35L knockout mouse resulted in early embryonic lethality (PMID 25434475;31712251). Microphthalmia and multiple other anomalies. Sources: Expert Review |
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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 v0.4699 | NCAPD2 |
Zornitza Stark gene: NCAPD2 was added gene: NCAPD2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NCAPD2 were set to 31056748; 27737959; 28097321 Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive; OMIM #617983 Review for gene: NCAPD2 was set to GREEN Added comment: Three families reported: 1 family with 2 sibs with microcephaly and ID, and homozygous NCAPD2 mutation, which segregated with disease. No functional evidence. 1 family with 1 affected and homozygous NCAPD2 mutation, which segregated with disease. Patient fibroblasts showed impaired chromosome segregation and abnormal recovery from mitotic condensation compared to controls. 1 family with 2 sibs with microcephaly, growth retardation, and ID, and homozygous NCAPD2 mutation, which segregated with disease. Functional studies of the variants and studies of patient cells were not performed. IUGR reported. Sources: Expert Review |
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| Fetal anomalies v0.4686 | PTPN23 |
Belinda Chong gene: PTPN23 was added gene: PTPN23 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065 Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890 Review for gene: PTPN23 was set to GREEN gene: PTPN23 was marked as current diagnostic Added comment: Onset at birth or early infancy. Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum. Sources: Literature |
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| Fetal anomalies v0.4686 | PPP1R15B |
Belinda Chong gene: PPP1R15B was added gene: PPP1R15B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPP1R15B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP1R15B were set to 26159176; 26307080; 27640355 Phenotypes for gene: PPP1R15B were set to Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817 Review for gene: PPP1R15B was set to AMBER gene: PPP1R15B was marked as current diagnostic Added comment: Three unrelated families reported, two with the same variant. Phenotype in family reported in PMID 27640355 included infantile cirrhosis requiring transplantation. Sources: Literature |
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| Fetal anomalies v0.4532 | PCYT2 |
Belinda Chong gene: PCYT2 was added gene: PCYT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCYT2 were set to 31637422 Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive MIM#618770 Review for gene: PCYT2 was set to RED gene: PCYT2 was marked as current diagnostic Added comment: Brain imaging shows progressive cerebral and cerebellar atrophy however, normal initially. 5 individuals from 4 families reported with progressive neurologic disorder characterized by global developmental delay apparent from infancy, significant motor impairment, and progressive spasticity mainly affecting the lower limbs. Some never achieved walking, whereas others lost the ability to walk or walk with an unsteady gait. Additional features included variably impaired intellectual development with language difficulties, ocular anomalies, such as nystagmus and visual impairment, and seizures. Brain imaging shows progressive cerebral and cerebellar atrophy, as well as white matter hyperintensities. Overall poor growth, but only one individual reported with microcephaly -3SD, and head size appears relatively spared against other reported growth parameters. Sources: Literature |
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| Fetal anomalies v0.4404 | STT3A |
Krithika Murali gene: STT3A was added gene: STT3A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: STT3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STT3A were set to 34653363; 23842455; 30701557; 28424003 Phenotypes for gene: STT3A were set to Congenital disorder of glycosylation, type Iw, autosomal dominant - MIM#619714; Congenital disorder of glycosylation, type Iw, autosomal recessive - MIM#615596 Review for gene: STT3A was set to GREEN Added comment: Biallelic variants associated with an earlier onset of symptoms. PMID: 23842455 report IUGR in one infant. PMID: 28424003 - report 5 affected individuals from one family, birth growth parameters of 4/5 individuals suggestive of growth restriction/relative microcephaly. --- ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A) PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16). Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged). Sources: Literature |
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| Fetal anomalies v0.4372 | SLC35C1 |
Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature. Variable severity, some present in childhood. |
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| Fetal anomalies v0.4372 | SLC35C1 |
Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature. |
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| Fetal anomalies v0.4317 | TUBGCP2 |
Chirag Patel gene: TUBGCP2 was added gene: TUBGCP2 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TUBGCP2 were set to PMID: 31630790 Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM # 618737 Review for gene: TUBGCP2 was set to GREEN Added comment: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is an autosomal recessive neurologic disorder characterized by progressive microcephaly associated with abnormal facial features, hypotonia, and variable global developmental delay with impaired intellectual development. Brain imaging shows variable malformation of cortical development on the lissencephaly spectrum, mainly pachygyria and thin corpus callosum. 4 unrelated patients with homozygous or compound heterozygous mutations in the TUBGCP2 gene, found by WES and segregated with the disorder in all families. Functional studies of the variants were not performed, but analysis of patient fibroblasts derived from the patient with a splice site mutation demonstrated the production of several abnormal transcripts that were predicted to result in a loss of function. Sources: Expert list |
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| Fetal anomalies v0.4311 | VPS4A |
Chirag Patel gene: VPS4A was added gene: VPS4A was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to PMID: 33186543; 33186545 Phenotypes for gene: VPS4A were set to CIMDAG syndrome MIM# 619273 Review for gene: VPS4A was set to GREEN Added comment: CIMDAG syndrome is a multisystemic disorder characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. The associated hematologic abnormalities are variable, but are mostly consistent with congenital dyserythropoietic anemia. Eight unrelated patients with de novo heterozygous missense mutations in the VPS4A gene. Sources: Expert list |
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| Fetal anomalies v0.4303 | VPS51 |
Chirag Patel gene: VPS51 was added gene: VPS51 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS51 were set to PMID: 30624672; 31207318 Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606 Review for gene: VPS51 was set to AMBER Added comment: Pontocerebellar hypoplasia type 13 (PCH13) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment. Two families reported with bi-allelic variants in this gene. Sources: Expert list |
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| Fetal anomalies v0.4295 | YIF1B |
Chirag Patel gene: YIF1B was added gene: YIF1B was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YIF1B were set to PMID: 32006098; 26077767 Phenotypes for gene: YIF1B were set to Kaya-Barakat-Masson syndrome, MIM# 619125 Review for gene: YIF1B was set to GREEN Added comment: Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development, peripheral spasticity, dystonia, impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood. 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function. Sources: Expert list |
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| Fetal anomalies v0.4294 | NFIB |
Krithika Murali gene: NFIB was added gene: NFIB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NFIB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NFIB were set to 30388402; 33130023; 32902921 Phenotypes for gene: NFIB were set to Macrocephaly, acquired, with impaired intellectual development - MIM#618286 Review for gene: NFIB was set to GREEN Added comment: NFIB haploinsufficiency associated with syndromic ID. Macrocephaly and corpus callosum anomalies are recurrent phenotypic features. OMIM notes macrocephaly postnatal in onset, but review of published cases shows some instances of relative macrocephaly at birth. Also corpus callosal anomalies - agenesis and dysgenesis, noted on MRI-B in childhood but possibility of detecting this antenatally in future cases. 2 unrelated individuals reported with minor cardiac anomalies also. --- OMIM notes macrocephaly postnatal in onset. PMID: 30388402 - 18 individuals reported, of whom 11 had deletions of this gene and the rest had SNVs. Relative macrocephaly noted based on growth parameters in 4 individuals (e.g. x1 male with BW 22nd centile and HC 99th centile in an apparently uncomplicated pregnancy) - macrocephaly became more pronounced with age. In addition, 2 individuals had congenital cardiac anomalies (x1 small VSD and x1 narrow pulmonary artery) and 2 individuals had complete agenesis of the corpus callosum. 33130023 - Report one affected individual. Birth weight was 4.13 kg (Z-score 1.50, 93rd percentile), length was 52 cm (Z-score 1.12, 87th percentile) and his head circumference was 37 cm (Z-score 2.00, 98th percentile). MRI-B at 12 months confirmed agenesis of the corpus callosum 32902921 - report one patient with normal antenatal history, no birth HC provided, macrocephaly noted at 7 months. MRI-B showed mild dysgensis of the corpus callosum age 5. 2nd unrelated patient's birth weight 3.43 kg(57th centile,Zscore 0.17), length 52.8 cm (94th centile, Zscore1.54), and OFC 37.5 cm (99th centile,Zscore 2.39). MRI-B age 5 showed dysgenesis of the corpus callosum. Sources: Literature |
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| Fetal anomalies v0.4161 | RAD50 |
Chirag Patel gene: RAD50 was added gene: RAD50 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD50 were set to PMID: 19409520; 32212377; 33378670 Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078; MONDO:0013118 Review for gene: RAD50 was set to GREEN Added comment: Nijmegen breakage syndrome-like disorder (NBSLD) is an autosomal recessive disorder characterized by severe prenatal growth retardation and persistent postnatal growth restriction, congenital microcephaly, borderline to mildly impaired intellectual development, normal sexual development, and radioresistant DNA synthesis with no immunodeficiency, myelodysplasia, or early neurodegeneration. Three unrelated families reported. Sources: Expert list |
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| Fetal anomalies v0.3681 | GRIK2 | Zornitza Stark Phenotypes for gene: GRIK2 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 to Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3677 | GRIK2 | Zornitza Stark reviewed gene: GRIK2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3617 | DEAF1 | Zornitza Stark Phenotypes for gene: DEAF1 were changed from Autism, intellectual disability, basal ganglia dysfunction and epilepsy; MENTAL RETARDATION, AUTOSOMAL DOMINANT 24 to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.3096 | PPP3CA | Zornitza Stark Phenotypes for gene: PPP3CA were changed from Severe Neurodevelopmental Disease with Seizures to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3094 | PPP3CA | Zornitza Stark reviewed gene: PPP3CA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3031 | PPP3CA | Belinda Chong reviewed gene: PPP3CA: Rating: AMBER; Mode of pathogenicity: None; Publications: 29432562, 28942967, 28942967; Phenotypes: Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265, Developmental and epileptic encephalopathy 91 617711; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3022 | PLAA |
Zornitza Stark changed review comment from: NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy. At least 5 families reported.; to: NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy. At least 5 families reported. Mouse model. |
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| Fetal anomalies v0.2993 | PGAP1 | Zornitza Stark Phenotypes for gene: PGAP1 were changed from Intellectual disability, encephalopathy, impaired GPI-anchor maturation to Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, MIM# 615802 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2933 | ST3GAL3 | Zornitza Stark changed review comment from: PMID: 31584066 reports on two di-chorionic infant twins p.Y220*, presenting with epileptic encephalopathy with impaired neuromotor development.; to: Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2839 | IARS | Alison Yeung Phenotypes for gene: IARS were changed from Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, 617093 to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, OMIM# 617093 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2838 | IARS | Alison Yeung reviewed gene: IARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27426735, 27891590; Phenotypes: Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2799 | MATN3 | Zornitza Stark Phenotypes for gene: MATN3 were changed from Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728); Epiphyseal dysplasia, multiple, 5 (MIM#607078) to Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type, MIM# 608728 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2797 | MATN3 | Zornitza Stark reviewed gene: MATN3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type, MIM# 608728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2623 | MED13L | Zornitza Stark Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2619 | MED13L | Zornitza Stark reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2504 | ZIC1 | Seb Lunke Phenotypes for gene: ZIC1 were changed from CRANIOSYNOSTOSIS 6 to Structural brain anomalies with impaired intellectual development and craniosynostosis; OMIM#618736 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2472 | YWHAG |
Zornitza Stark changed review comment from: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia. PMID: 33393734 8x patients all de novo missense. Patient cohort shared with PMID: 31926053 7/8 have mild-mod ID 6/8 have seizures PMID: 33767733 1x de novo missense and 1x nonsense familial with 6 affecteds. All patients from this study have febrile seizures but normal intelligence and motor development. PMID: 33590706 1x de novo. mild ID and generalized tonic–clonic seizures; to: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia. PMID: 33393734 8x patients all de novo missense. Patient cohort shared with PMID: 31926053 7/8 have mild-mod ID 6/8 have seizures PMID: 33767733 1x de novo missense and 1x nonsense familial with 6 affecteds. All patients from this study have febrile seizures but normal intelligence and motor development. PMID: 33590706 1x de novo. mild ID and generalized tonic–clonic seizures Onset in first year of life. |
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| Fetal anomalies v0.2411 | TRMT10A | Zornitza Stark Phenotypes for gene: TRMT10A were changed from Microcephaly, short stature, and impaired glucose metabolism 1 to Microcephaly, short stature, and impaired glucose metabolism 1, MIM# 616033; MONDO:0000208 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2354 | TBR1 |
Zornitza Stark changed review comment from: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039).; to: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039). Pachygyria in some individuals. |
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| Fetal anomalies v0.2352 | MED13L | Ain Roesley reviewed gene: MED13L: Rating: AMBER; Mode of pathogenicity: None; Publications: 33930262, 29959045, 32646507; Phenotypes: Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2325 | DPM3 | Zornitza Stark Phenotypes for gene: DPM3 were changed from ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937 to Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2265 | DDX6 | Zornitza Stark Phenotypes for gene: DDX6 were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder with impaired language and dysmorphic facies, MIM#618653 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2257 | HYLS1 |
Zornitza Stark changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Amber rating given only single founder variant reported with a hydrocephalus phenotype with supporting functional data from multiple animal models indicative of ciliopathy.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Overall, sufficient evidence that variants in this gene cause a ciliopathy. |
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| Fetal anomalies v0.1623 | APOPT1 |
Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in childhood.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in early childhood. |
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| Fetal anomalies v0.1623 | APOPT1 |
Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in childhood. |
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| Fetal anomalies v0.1469 | MIB1 |
Krithika Murali gene: MIB1 was added gene: MIB1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIB1 were set to 33057194 Phenotypes for gene: MIB1 were set to Congenital heart disease Review for gene: MIB1 was set to AMBER Added comment: Last reviewed March and Dec 2021 - no additional evidence Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert list, Literature |
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| Fetal anomalies v0.1469 | FBRSL1 |
Krithika Murali gene: FBRSL1 was added gene: FBRSL1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBRSL1 were set to 32424618; 34805182 Phenotypes for gene: FBRSL1 were set to Congenital malformations; congenital heart defect Review for gene: FBRSL1 was set to GREEN Added comment: Associated with novel malformation and intellectual disability syndrome. Three unrelated children with de novo PTCs that escape NMD, with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations - 2/3 had heart defects (ASD, VSD), cleft palate and hearing impairement. Supported by Xenopus oocyte functional studies Sources: Literature |
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| Fetal anomalies v0.1465 | AIRE | Zornitza Stark Marked gene: AIRE as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1465 | AIRE | Zornitza Stark Gene: aire has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1465 | AIRE | Zornitza Stark Phenotypes for gene: AIRE were changed from AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, MIM# 240300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1464 | AIRE | Zornitza Stark reviewed gene: AIRE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, MIM# 240300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1361 | TP73 |
Krithika Murali gene: TP73 was added gene: TP73 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TP73 were set to 31130284; 34077761 Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly - MIM# 619466 Review for gene: TP73 was set to GREEN Added comment: 7 unrelated families reported. In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls. Clinical features included recurrent respiratory infections and respiratory dysfunction caused by defective mucociliary clearance in early childhood. Affected individuals also had neurologic features, such as impaired intellectual development and central hypotonia, associated with structural brain abnormalities, most notably lissencephaly and thin or absent corpus callosum. Sources: Literature |
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| Fetal anomalies v0.1223 | CHRNA3 | Zornitza Stark Phenotypes for gene: CHRNA3 were changed from Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, 191800 to Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, MIM# 191800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1220 | CHRNA3 |
Zornitza Stark changed review comment from: Five individuals from three unrelated families.; to: Five individuals from three unrelated families. Onset is in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension. |
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| Fetal anomalies v0.1220 | CHRNA3 | Zornitza Stark reviewed gene: CHRNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31708116; Phenotypes: Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, MIM# 191800; Mode of inheritance: 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 v0.957 | 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 v0.610 | 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 v0.487 | MATN3 | Seb Lunke Phenotypes for gene: MATN3 were changed from MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 5 to Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728); Epiphyseal dysplasia, multiple, 5 (MIM#607078) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.448 | MATN3 | Daniel Flanagan reviewed gene: MATN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31724101, 32025536, 11968079, 14729835; Phenotypes: Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (MIM#608728), Epiphyseal dysplasia, multiple, 5 (MIM#607078); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.354 | C21orf2 |
Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. New HGNC approved name is CFAP410.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. New HGNC approved name is CFAP410. Thoracic hypoplasia is present at birth so relevant to this panel. |
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| Fetal anomalies v0.0 | AIRE |
Zornitza Stark gene: AIRE was added gene: AIRE was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: AIRE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AIRE were set to AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1 |
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| Fetal anomalies v0.0 | TRMT10A |
Zornitza Stark gene: TRMT10A was added gene: TRMT10A was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: TRMT10A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TRMT10A were set to Microcephaly, short stature, and impaired glucose metabolism 1 |
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| Fetal anomalies v0.0 | PGAP1 |
Zornitza Stark gene: PGAP1 was added gene: PGAP1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: PGAP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PGAP1 were set to Intellectual disability, encephalopathy, impaired GPI-anchor maturation |
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| Fetal anomalies v0.0 | DPM3 |
Zornitza Stark gene: DPM3 was added gene: DPM3 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: DPM3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DPM3 were set to ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937 |
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| Fetal anomalies v0.0 | CHRNA3 |
Zornitza Stark gene: CHRNA3 was added gene: CHRNA3 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CHRNA3 were set to Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, 191800 |
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| Fetal anomalies v0.0 | IARS |
Zornitza Stark gene: IARS was added gene: IARS was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IARS were set to 27426735 Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, 617093 |
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