TABLE 2.
Variants of unknown clinical significance likely related to the phenotype and shared by both partners
| Case ID | Phenotype | Indication | Gene | Variants | OMIM disease | Serial no. |
|---|---|---|---|---|---|---|
| 1 | Recurrent neonatal deaths | ND | WDR34 | c.544C > T p.R182W | Short‐rib thoracic dysplasia 11 with or without polydactyly | 1 |
| 2 | Oligohydramnios, dysmorphic facial features, midline cleft lip, agenesis of corpus callosum, occipital encephalocele. | ND | CC2D2A | c.4531T > C (p.Trp1511Arg) | Joubert syndrome‐9 | 2 |
| 3 | IUGR, subcutaneous edema, abnormal position of upper and lower limbs with no movement. | RPL | AGRN | c.5948C > T (p.Thr1983Met) | Congenital myasthenic syndrome‐8 | 3 |
| 4 | Intrauterine fetal death, IUGR. | RPL | ZMIZ2/KIAA1886 | c.1270C > T (p.Gln424*) | 4 | |
| 5 | Recurrent neonatal deaths. | ND | GORAB | c.306dup (p.Pro103Thrfs*20) | Gerodermia osteodysplastica | 5 |
| 6 | Recurrent neonatal deaths. | ND | QARS1 | c.316G > A (p.Asp106Asn) | Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA) | 6 |
| ACACA | c.81A > G (p.Ile27Met) | Acetyl‐CoA carboxylase deficiency | 7 | |||
| 7 | Central hypotonia, scoliosis, cerebellar hypoplasia, 2–3 toe syndactyly, atrial septal defect, PDA, abnormal ear morphology, high palate. | ND | PAX1 | c.95C > T p.(A32V) | Otofaciocervical syndrome 2 | 8 |
| MSRB3 | c.2T > G/likely pathogenic | Autosomal recessive deafness‐74 | 9 | |||
| MOCOS | c.894CA (p.Y298*) likely pathogenic | Molybdenum cofactor sulfurase | 10 | |||
| 8 | 2X Hydrops fetalis, polyhydramnios, multiple congenital anomalies. | RPL | KLHL40 | c.35G > T p.(Arg12Leu) | AR nemaline myopathy type 8 | 11 |
| 9 |
1: Dandy‐Walker malformation, polyhydramnios, stillbirth; 2: IUFD with CNS anomalies. 3: Absent septum pellucidum; agenesis of corpus callosum; aplasia/hypoplasia of the corpus callosum; cerebellar vermis hypoplasia; Dandy‐Walker malformation; dilated third ventricle; echogenic fetal bowel; enlarged cisterna magna; ventriculomegaly. |
RPL | FH | c.1043G > A p.(Gly348Asp) | Fumarate hydratase | 12 |
| FKRP | c.1061G > A p.(Gly354Glu) | Congenital muscular dystrophy‐dystroglycanopathy with or without impaired intellectual development | 13 | |||
| 10 | Transposition of great arteries, abnormal heart valves, agenesis of corpus callosum, holoprosencephaly, hydrocephalus, IUGR. | IUFD | FKTN | c.44T > G P.(Leu15Arg) | Muscular dystrophy‐dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 | 14 |
| DOCK6 | c.356A > G P.(Asp119Gly) | Adams‐Oliver syndrome‐2 | 15 | |||
| 11 | IUFD with increased NT, ventriculomegaly, multicyclic dysplastic kidney and short long bone. | IUFD | DHX34 | c. 1399G > A P. D467N | 16 | |
| 12 | Brain anomalies, FTT, dilated lateral ventricles, partial agenesis of the corpus callsum, EEG abnormalities, IUGR, bilateral hearing loss, optic atrophy. | IUFD | DOCK7 | c.1591G > A | Developmental and Epileptic Encephalopathy‐23 (DEE23) | 17 |
| 13 | 5X; IUFD at 7 months, boy with short limbs and hydrocephalus; IUFD at 6 months with short limbs; IUFD at 24 weeks with massive fetal edema, abnormal skeletal system and bilateral dilated renal pelvis; IUFD at 27 weeks, fetal edema, ascites and short limbs. | IUFD | CHAT | c.1300G > A (p.Gly434Ser) | Myasthenic syndrome, congenital, 6, presynaptic | 18 |
| 14 | Recurrent spontaneous abortions. Couple had 2 children affected with seizures, hypotonia, global developmental delay, recurrent aspiration pneumonia, constipation, both children deceased. | ND RPL | KIAA0556 | c.1777T > C p.(Tyr593His) | Joubert syndrome‐26 | 19 |
| 15 | Recurrent neonatal deaths. | ND | NDUFAF3 | c.481C > G (p.Arg161Gly) | Mitochondrial respiratory chain complex I | 20 |
| 16 | Recurrent neonatal deaths. | ND | GBA | c.520T > A (p.Tyr174Asn) | Gaucher disease | 21 |
| 17 | Abnormal VLCFA (? diagnosis‐Zellweger syndrome). | ND | PEX1 | c.1240_1359del (p.Ile414_Leu453del) | Peroxisomal biogenesis disorders 1A | 22 |
| 18 | Agenesis of corpus callosum associated with white matter and brainstem abnormal signal. | ND | NDUFAF5 | c.737T > A (p.Leu246Gln) | Mitochondrial respiratory chain complex I deficiency nuclear type 16 | 23 |
| 19 | Microcephaly, hypotonia, encephalopathy, increased CSF lactate level and 3‐methylglutaconic aciduria. | ND | HTRA2 | c.818_820del (p.Leu273del) | 3‐Methylglutaconic aciduria type VIII (MGCA8 | 24 |
| 20 | Neonatal death with hyperammonemia. | ND | CPS1 | c.211T > C p.(Ser71Pro) | Carbamoyl phosphate synthetase I | 25 |
| 21 | Recurrent miscarriage. | RPL | CCDC88C | c.5059‐2A > G | congenital hydrocephalus‐1 | 26 |
|
22 23 |
2X early neonatal death with hypotonia and recurrent respiratory infections and respiratory distress. | ND | POLR3A | c.1895G > T (p.Cys632Phe) | Leukodystrophy, hypomyelinating, 7 (HLD7) | 27 |
| 24 |
Abnormal facial features; Failure to thrive; feeding difficulty,Laryngomalacia; Motor delay; passed away with Respiratory compromise. 1: Stillbirth; Brother 2: Stillbirth; Brother 3: Stillbirth; Mother: Spontaneous abortion; Sister 1: Stillbirth; Sister 2: Stillbirth; Sister 3: Stillbirth Siblings affected. |
ND | UNC80 | c.5254C > T p.(Leu1752Phe) | Infantile hypotonia with psychomotor retardation and characteristic facies‐2 | 28 |
| 15 | Recurrent neonatal deaths. | ND | TMEM231 | c.685C > G:p.(Pro229Ala) |
Ciliopathic diseases Meckel syndrome 11 |
29 |
| 25 | Previous 3X IUFD Multiple congenital anomalies and neonatal death with brain atrophy, esophageal atresia, heterotaxy; hypoplastic right heart IUFD | ND | DCHS1 | c.4552C > G p.(Arg1518Gly) | Multiple congenital anomalies | 30 |
| 26 | Multiple congenital anomalies and early death. | ND | KIAA0556 | NM_015202.3:c.1768G > A:p.(Val590Met) | AR Joubert syndrome type 26 | 31 |
Abbreviations: RPL: recurrent pregnancy loss including miscarriage and IUFD; ND: neonatal death; OMIM, online Mendelian inheritance in man; PCS: preconception screening in the presence of cousins with a genetic condition.