List of genetic variants and clinical details of individuals with a likely diagnosis
| Patient ID # | Family # | Gender/age at inclusion or death* or termination of pregnancy (TOP) | Affected gene | Reference sequence ID | DNA change | Predicted AA change | Variant classification (ACMG) | Zygosity | Published (PMID)/not published | OMIM phenotype (mode of inheritance) | Aetiological classification (OMIM diseases) | Prenatal abnormalities | Joint contractures (prenatal or postnatal) | Dysmorphic features | Neurological abnormalities | Other features |
| F1:II.1 | 1 | F/TOP (17 WGA) | ACTA1 | NM_001100.4 | c.[226G>C];[=] | p.[(Gly76Arg)];[(=)] | Likely pathogenic | Heterozygous (maternal mosaicism; mother with generalised, asymmetric structural myopathy but no contractures) | Not published to date | #616852 (AD), #255310, #161800 (AD +AR) | Myogenic (myopathy, nemaline myopathy 3) | RFM, ulnar deviation of the hands | Shoulders, elbows, wrists, fingers, hips, talipes equinovarus (bilateral) | Macrocephaly, hypertelorism, telecanthus, protrusio bulbi, micrognathia and retrognathia, short philtrum, cleft palate, low-set ears, microstomia, pterygia at axillae and elbows, clinodactyly, camptodactyly | − | Amyodysplasia of abdominal wall, spine muscles, and diaphragm, pulmonary hypoplasia, pectus carinatum, atrioseptal defect, anal ectopia, scoliosis |
| F2:II.1 | 2 | M/0 month (33 WGA)* | CHAT | NM_020984.3 | c.[3G>A];[487C>T] | p.[(Met1?)];[(Arg163Trp)] | Likely pathogenic, VUS | Compound heterozygous | Not published to date/not published to date | #254210 (AR) | Neuromuscular junction (congenital myasthenic syndrome 6) | RFM, polyhydramnios, pulmonary hypoplasia, hydrops fetalis | Multiple joint contractures, rocker-bottom feet | − | − | RI, pulmonary hypoplasia |
| F2:II.2 | 2 | F/TOP (23 WGA) | CHAT | NM_020984.3 | c.[3G>A];[487C>T] | p.[(Met1?)];[(Arg163Trp)] | Likely pathogenic, VUS | Compound heterozygous | Not published to date/not published to date | #254210 (AR) | Neuromuscular junction (congenital myasthenic syndrome 6) | RFM, velamentous insertion, lymphoedema of the feet, scalp oedema | Wrists, rocker-bottom feet | Micrognathia and retrognathia, long philtrum | − | Pulmonary hypoplasia, flexion anomaly of both hands |
| F3:II.1 | 3 | M/TOP (25 WGA) | GPC3 | NM_004484.3 | c.[1666G>C];[0] | p.[(Gly556Arg)];[(0)] | Likely pathogenic | Hemizygous (maternal inherited) | Not published to date | #312870 (X-linked) | Syndromic malformation (Simpson-Golabi-Behmel syndrome) | RFM | Wrists, knees, talipes equinovarus (bilateral) | − | − | Echogenic areas in the myocardium of the ventricular septum and left ventricle |
| F4:II.1 | 4 | F/9 years | MAGEL2 | NM_019066.5 | c.[1996dup];[=] | p.[(Gln666Profs*47)];[(=)] | Pathogenic | Heterozygous (paternal allele affected), de novo | Published (PMID: 25473036, 27195816) | #615547 (AD, imprinting) | Syndromic malformation (Schaaf-Yang syndrome) | RFM, ND | Elbows, wrists, fingers, talipes equinovarus (bilateral) | Large ears, premature craniosynostosis, camptodactyly, clinodactyly | Intellectual disability, motor and speech developmental delay, muscular hypotonia, hypotrophy of shoulder muscles | Hydronephrosis (bilateral), anal stenosis, laryngomalacia, scoliosis, strabismus |
| F5:II.1 | 5 | M/TOP (25 WGA) | MYH3 | NM_002470.4 | c.[2015G>A];[=] | p.[(Arg672His)];[(=)] | Pathogenic | Heterozygous, de novo | Published (PMID: 16642020, 28584669, 26996280) | #193700, #178110 (AD) | Myogenic (distal arthrogryposis 2A) | RFM | Wrists, knees, ankles | Abnormal facial profile with long philtrum | − | Bent lower leg bones (bilateral) |
| F6:II.1 | 6 | M/8 months | NALCN | NM_052867.4 | c.[3522A>T|;[=] | p.[(Arg1174Ser)];[(=)] | Likely pathogenic | Heterozygous, de novo | Not published to date; patient listed in DECIPHER (ID 388888) | #616266 (AD) | Syndromic malformation (congenital contractures of the limbs and face, hypotonia and developmental delay) | Polyhydramnios, insulin-dependent diabetes mellitus | Bilateral adducted thumbs and contracted third fingers (improved with age) | Round face, mild hypertelorism, short palpebral fissures, microstomia | Severe global developmental delay, at 3 8/12 years no unsupported sitting, crawling, standing or walking, no speech, reduced comprehension; oromandibular dystonia | Normal birth measurements at birth (39+2), Apgar 9/9/9 but problems with respiratory adaptation (tachydyspnoeia, inspiratory stridor); laryngomalacia as newborn, 2 times laser treatment; now all measurements low, especially short stature, at 3 8/12 years weight −2.3 SD, length −3.9 SD, Occipitofrontal circumference −2.5 SD |
| F7:II.1 | 7 | M/TOP (18 WGA) | NEB | NM_001271208.2 | c.[3084C>G];[3726dup] | p.[(Tyr1028*)];[(Ser1243Leufs*16)] | Pathogenic, pathogenic | Compound heterozygous | Not published to date/not published to date | #256030, #619334 (AR) | Myogenic (arthrogryposis multiplex congenita 6, nemaline myopathy 2) | RFM, IUGR, cystic hygroma | Suspected multiple joint contractures | − | − | Short and single umbilical artery |
| F8:II.1 | 8 | M/2.5 months* | NEK9 | NM_033116.5 | c.[874–2A>G];[1432delC] | p.[(?)];[(Leu478Serfs*18)] | Likely pathogenic, pathogenic | Compound heterozygous | Not published to date | #614262, #617022 (AR) | Neurogenic (lethal congenital contracture syndrome 10) | RFM, polyhydramnios | Elbows, wrists, fingers, hips, knees, ankles | Retrogenia, macroglossia, camptodactyly | Seizures, muscular hypertonia | Pulmonary hypoplasia, RI, pulmonary stenosis, cardiomegaly, bilateral hydronephrosis, unilateral inguinal hernia, anal prolapse |
| F9:II.1 | 9 | F/2 months | PIEZ02 | NM_022068.4 | c.[8057G>A];[=] | p.[(Arg2686His)];[(=)] | Pathogenic | Heterozygous, (inherited from similarly affected mother) | Published (PMID: 24726473, 27714920) | #114300, #108145 (AD), #617146 (AR) | Neurogenic (distal arthrogryposis 3) | RFM | Wrists, hips, knees, talipes equinovarus (bilateral) | Camptodactyly | − | − |
| F10:II.1 | 10 | F/TOP (21 WGA) | SLC6A9 | NM_201649.3 | c.[352G>A];[352G>A] | p.[(Val118Met)];[(Val118Met)] | Likely pathogenic | Homozygous | This case (PMID: 32712301) | #617301 (AR) | Neurogenic (glycine encephalopathy) | RFM, polyhydramnios, cystic structures in knees and elbows, increased nuchal translucency | Multiple joint contractures, talipes equinovarus (bilateral) | ND (autopsy not performed) | − | − |
| F10:II.2 | 10 | M/TOP (18 WGA) | SLC6A9 | NM_201649.3 | c.[352G>A];[352G>A] | p.[(Val118Met)];[(Val118Met)] | Likely pathogenic | Homozygous | This case (PMID: 32712301) | #617301 (AR) | Neurogenic (glycine encephalopathy) | RFM, polyhydramnios, increased nuchal translucency | Shoulders, elbows, wrists, fingers, hips, knees, talipes equinovarus (bilateral) | Micrognathia and retrognathia, talipes equinovarus (bilateral) | − | − |
| F11:II.1 | 11 | M/2 months | SRD5A3 | NM_024592.4 | c.[829T>C];[829T>C] | p.[(Trp277Arg)];[(Trp277Arg)] | Likely pathogenic | Homozygous | Not published to date | #612379, #612713 (AR) | Neurogenic (congenital disorder of glycosylation type Iq, Kahrizi syndrome) | RFM, IUGR, human tail, hypertrichosis | Elbows, wrists, fingers, hips, knees | Micrognathia and retrognathia, dysplastic low-set ears, thin upper lip, sacral human tail, cleft palate, camptodactyly | Muscular hypertonia, wide cisterna magna, pathological oculomotor function and otoacoustic emissions | RI, NIV, laryngomalacia, retinal coloboma, myocardial hypertrophy, myocardial infarction, thymic hypoplasia, hyperglycaemia, insulin resistance, ichthyosis, cryptorchidism |
| F12:II.1 | 12 | F/2 months | TTN | NM_001267550.2 | c.[31034_31035del];[39 974–11T>G] | p.[(Tyr10345*)];[(?)] | Pathogenic, pathogenic | Compound heterozygous | Not published to date/published (PMID: 31660661) | #604145 (AD), #611705 (AR) | Myogenic (Salih myopathy) | RFM | Multiple joint contractures | Yes, not specified | Delayed motor development, muscular hypotonia | Not specified |
| F13:II.1 | 13 | F/7 months | TTN | NM_001267550.2 | c.[26 764C>T];[39 974–11T>G] | p.[(Arg8922*)];[(?)] | Likely pathogenic, pathogenic | Compound heterozygous | Not published to date/published (PMID: 31660661) | #604145 (AD), #611705 (AR) | Myogenic (Salih myopathy) | RFM, IUGR, oligohydramnios | Multiple joint contractures | Yes, not specified | Muscular hypotonia, generalised decreased muscle bulk | RI, NIV (post partum for 2 weeks) |
| Individuals carrying variants of unknown significance | ||||||||||||||||
| F14:II.1 | 14 | F/TOP (27 WGA) | SLC6A9 | NM_201649.3 | c.[167C>G];[245C>G] | p.[(Ser56Cys)];[(Ala82Gly)] | VUS/VUS | Father carries only the c.245C>G variant; mother not available | Not published to date/not published to date | #617301 (AR) | Neurogenic (glycine encephalopathy) | RFM, retrognathia | Elbows, wrists, crossed fingers, hips, knees, talipes equinovarus (bilateral) | Retrognathia | Signs of congenital myasthenic syndrome | − |
| F15:II.1 | 15 | F/8 years | BICD2 | NM_001003800.2 | c.[2105A>G];[=] | p.[(Gln702Arg)];[(=)] | VUS | Parents not tested | Not published to date but listed in ClinVar (likely pathogenic) | #615290 (AD), #618291 (AD) | Neurogenic (spinal muscular atrophy 2) | RFM | Hips, knees, ankles, talipes equinovarus (left), sickle foot (right) | Prominent forehead, four-finger furrow, crossed 2nd and 3rd toe | Atonic seizures, cognitive impairment, psychomotor developmental delay, global muscular hypotonia, atrophy of leg muscles, reduced muscle reflexes of the lower extremity, positive Babinsky sign (bilateral) | Bilateral hip dislocation, short stature, two café au lait spots |
List of genetic variants and clinical details of the cohort sorted by disease-causal genetic defects in known FA-associated genes and cases with variants of unknown significance. Provided information includes patient ID, family ID, gender, age at inclusion or death in months and years or termination of pregnancy in WGA. Age 0 denotes children dying <1 month after birth. Additionally, provided data include the affected gene, RefSeq ID, DNA change, AA change, variant classification (ACMG scores), gene-associated OMIM phenotypes, mode of inheritance and zygosity. Furthermore, it is indicated whether variants have already been published independently (with corresponding PMID) or not. The variant nomenclature is in accordance with Human Genome Variation Society standards.
*Death.
AA, amino acid; ACMG, American College of Medical Genetics and Genomics; AD, autosomal dominant; AR, autosomal recessive; F, female; FA, fetal akinesia; IUGR, intrauterine growth restriction; M, male; ND, no data; NIV, non-invasive ventilation; PMID, PubMed ID; RFM, reduced fetal movements; RI, respiratory insufficiency; VUS, variant of uncertain significance in the ACMG classification system; WGA, weeks of gestational age.