Table 1

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 geneReference sequence IDDNA changePredicted AA changeVariant classification (ACMG)ZygosityPublished (PMID)/not publishedOMIM phenotype (mode of inheritance)Aetiological classification (OMIM diseases)Prenatal abnormalitiesJoint contractures (prenatal or postnatal)Dysmorphic featuresNeurological abnormalitiesOther features
F1:II.11F/TOP (17 WGA) ACTA1 NM_001100.4c.[226G>C];[=]p.[(Gly76Arg)];[(=)]Likely pathogenicHeterozygous (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 handsShoulders, 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, camptodactylyAmyodysplasia of abdominal wall, spine muscles, and diaphragm, pulmonary hypoplasia, pectus carinatum, atrioseptal defect, anal ectopia, scoliosis
F2:II.12M/0 month (33 WGA)* CHAT NM_020984.3c.[3G>A];[487C>T]p.[(Met1?)];[(Arg163Trp)]Likely pathogenic, VUSCompound heterozygousNot published to date/not published to date#254210 (AR)Neuromuscular junction (congenital myasthenic syndrome 6)RFM, polyhydramnios, pulmonary hypoplasia, hydrops fetalisMultiple joint contractures, rocker-bottom feetRI, pulmonary hypoplasia
F2:II.22F/TOP (23 WGA) CHAT NM_020984.3c.[3G>A];[487C>T]p.[(Met1?)];[(Arg163Trp)]Likely pathogenic, VUSCompound heterozygousNot published to date/not published to date#254210 (AR)Neuromuscular junction (congenital myasthenic syndrome 6)RFM, velamentous insertion, lymphoedema of the feet, scalp oedemaWrists, rocker-bottom feetMicrognathia and retrognathia, long philtrumPulmonary hypoplasia, flexion anomaly of both hands
F3:II.13M/TOP (25 WGA) GPC3 NM_004484.3c.[1666G>C];[0]p.[(Gly556Arg)];[(0)]Likely pathogenicHemizygous (maternal inherited)Not published to date#312870 (X-linked)Syndromic malformation (Simpson-Golabi-Behmel syndrome)RFMWrists, knees, talipes equinovarus (bilateral)Echogenic areas in the myocardium of the ventricular septum and left ventricle
F4:II.14F/9 years MAGEL2 NM_019066.5c.[1996dup];[=]p.[(Gln666Profs*47)];[(=)]PathogenicHeterozygous (paternal allele affected), de novoPublished (PMID: 25473036, 27195816)#615547 (AD, imprinting)Syndromic malformation (Schaaf-Yang syndrome)RFM, NDElbows, wrists, fingers, talipes equinovarus (bilateral)Large ears, premature craniosynostosis, camptodactyly, clinodactylyIntellectual disability, motor and speech developmental delay, muscular hypotonia, hypotrophy of shoulder musclesHydronephrosis (bilateral), anal stenosis, laryngomalacia, scoliosis, strabismus
F5:II.15M/TOP (25 WGA) MYH3 NM_002470.4c.[2015G>A];[=]p.[(Arg672His)];[(=)]PathogenicHeterozygous, de novoPublished (PMID: 16642020,
28584669, 26996280)
#193700, #178110 (AD)Myogenic (distal arthrogryposis 2A)RFMWrists, knees, anklesAbnormal facial profile with long philtrumBent lower leg bones (bilateral)
F6:II.16M/8 months NALCN NM_052867.4c.[3522A>T|;[=]p.[(Arg1174Ser)];[(=)]Likely pathogenicHeterozygous, de novoNot 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 mellitusBilateral adducted thumbs and contracted third fingers (improved with age)Round face, mild hypertelorism, short palpebral fissures, microstomiaSevere global developmental delay, at 3 8/12 years no unsupported sitting, crawling, standing or walking, no speech, reduced comprehension; oromandibular dystoniaNormal 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.17M/TOP (18 WGA) NEB NM_001271208.2c.[3084C>G];[3726dup]p.[(Tyr1028*)];[(Ser1243Leufs*16)]Pathogenic, pathogenicCompound heterozygousNot published to date/not published to date#256030, #619334 (AR)Myogenic (arthrogryposis multiplex congenita 6, nemaline myopathy 2)RFM, IUGR, cystic hygromaSuspected multiple joint contracturesShort and single umbilical artery
F8:II.18M/2.5 months* NEK9 NM_033116.5c.[874–2A>G];[1432delC]p.[(?)];[(Leu478Serfs*18)]Likely pathogenic, pathogenicCompound heterozygousNot published to date#614262, #617022 (AR)Neurogenic (lethal congenital contracture syndrome 10)RFM, polyhydramniosElbows, wrists, fingers, hips, knees, anklesRetrogenia, macroglossia, camptodactylySeizures, muscular hypertoniaPulmonary hypoplasia, RI, pulmonary stenosis, cardiomegaly, bilateral hydronephrosis, unilateral inguinal hernia, anal prolapse
F9:II.19F/2 months PIEZ02 NM_022068.4c.[8057G>A];[=]p.[(Arg2686His)];[(=)]PathogenicHeterozygous, (inherited from similarly affected mother)Published (PMID: 24726473, 27714920)#114300, #108145 (AD), #617146 (AR)Neurogenic (distal arthrogryposis 3)RFMWrists, hips, knees, talipes equinovarus (bilateral)Camptodactyly
F10:II.110F/TOP (21 WGA) SLC6A9 NM_201649.3c.[352G>A];[352G>A]p.[(Val118Met)];[(Val118Met)]Likely pathogenicHomozygousThis case (PMID: 32712301)#617301 (AR)Neurogenic (glycine encephalopathy)RFM, polyhydramnios, cystic structures in knees and elbows, increased nuchal translucencyMultiple joint contractures, talipes equinovarus (bilateral)ND (autopsy not performed)
F10:II.210M/TOP (18 WGA) SLC6A9 NM_201649.3c.[352G>A];[352G>A]p.[(Val118Met)];[(Val118Met)]Likely pathogenicHomozygousThis case (PMID: 32712301)#617301 (AR)Neurogenic (glycine encephalopathy)RFM, polyhydramnios, increased nuchal translucencyShoulders, elbows, wrists, fingers, hips, knees, talipes equinovarus (bilateral)Micrognathia and retrognathia, talipes equinovarus (bilateral)
F11:II.111M/2 months SRD5A3 NM_024592.4c.[829T>C];[829T>C]p.[(Trp277Arg)];[(Trp277Arg)]Likely pathogenicHomozygousNot published to date#612379, #612713 (AR)Neurogenic (congenital disorder of glycosylation type Iq, Kahrizi syndrome)RFM, IUGR, human tail, hypertrichosisElbows, wrists, fingers, hips, kneesMicrognathia and retrognathia, dysplastic low-set ears, thin upper lip, sacral human tail, cleft palate, camptodactylyMuscular hypertonia, wide cisterna magna, pathological oculomotor function and otoacoustic emissionsRI, NIV, laryngomalacia, retinal coloboma, myocardial hypertrophy, myocardial infarction, thymic hypoplasia, hyperglycaemia, insulin resistance, ichthyosis, cryptorchidism
F12:II.112F/2 months TTN NM_001267550.2c.[31034_31035del];[39 974–11T>G]p.[(Tyr10345*)];[(?)]Pathogenic, pathogenicCompound heterozygousNot published to date/published (PMID: 31660661)#604145 (AD), #611705 (AR)Myogenic (Salih myopathy)RFMMultiple joint contracturesYes, not specifiedDelayed motor development, muscular hypotoniaNot specified
F13:II.113F/7 months TTN NM_001267550.2c.[26 764C>T];[39 974–11T>G]p.[(Arg8922*)];[(?)]Likely pathogenic, pathogenicCompound heterozygousNot published to date/published (PMID: 31660661)#604145 (AD), #611705 (AR)Myogenic (Salih myopathy)RFM, IUGR, oligohydramniosMultiple joint contracturesYes, not specifiedMuscular hypotonia, generalised decreased muscle bulkRI, NIV (post partum for 2 weeks)
Individuals carrying variants of unknown significance
F14:II.114F/TOP (27 WGA) SLC6A9 NM_201649.3c.[167C>G];[245C>G]p.[(Ser56Cys)];[(Ala82Gly)]VUS/VUSFather carries only the c.245C>G variant; mother not availableNot published to date/not published to date#617301 (AR)Neurogenic (glycine encephalopathy)RFM, retrognathiaElbows, wrists, crossed fingers, hips, knees, talipes equinovarus (bilateral)RetrognathiaSigns of congenital myasthenic syndrome
F15:II.115F/8 years BICD2 NM_001003800.2c.[2105A>G];[=]p.[(Gln702Arg)];[(=)]VUSParents not testedNot published to date but listed in ClinVar (likely pathogenic)#615290 (AD), #618291 (AD)Neurogenic (spinal muscular atrophy 2)RFMHips, knees, ankles, talipes equinovarus (left), sickle foot (right)Prominent forehead, four-finger furrow, crossed 2nd and 3rd toeAtonic 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.