Table 1.
Clinical and molecular data of the couples with PCT findings (confirmed and newly identified carrier couple states).
| Couple number | Country of origin | Consanguinity | Family history | Number of shared pathogenic variants | Shared pathogenic variant (boldface: novel, detected by PCT) | Disease (for novel findings without previously affected child: most likely associated disease associated with identified variant, based on previous reports of identical or similar variant) |
|---|---|---|---|---|---|---|
| 1 | Turkey | Double 1st cousins | One healthy daughter | 1 | Chr5(GRCh37):g.149359991C>T, NM_000112.3(SLC26A2):c.835C>T, p.(Arg279Trp) | Multiple epiphyseal dysplasia, type 4 (OMIM 226900) |
| 2 | Turkey | Double 1st cousins | One daughter homozygous for ATP8A2 variant | 2 |
Chr13(GRCh37):g.26151250C>T, NM_016529.5(ATP8A2):c.1756C>T, p.(Arg586*) Chr13(GRCh37):g.20763452A>G, NM_004004.5(GJB2):c.269T>C, p.(Leu90Pro) |
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 (OMIM 615268) Autosomal recessive deafness type 1 A (OMIM 220290) |
| 4 | Turkey | 1st cousins | One daughter homozygous for HGSNAT variant, three healthy children | 2 |
Chr8(GRCh37):g.43002207G>A, NG_009552.1(HGSNAT):c.234 + 1G>A, p.? Chr1(GRCh37):g.94473807C>T, NM_000350.2(ABCA4):c.5882G>A, p.(Gly1961Glu) |
Mucopolysaccharidosis type IIIC, Sanfilippo C (OMIM 252930) Stargardt disease 1 (OMIM 248200) |
| 6 | Turkey | 1st cousins | One son homozygous for ACOX1 variant, died at age five years | 2 | Chr17(GRCh37):g.73956446G>A, NM_004035.6(ACOX1):c.280C>T, p.(Arg94*) | Peroxisomal acyl-CoA oxidase deficiency (OMIM 264470) |
| 7 | Turkey | 2nd cousins | One daughter homozygous for ELP2 variant, one healthy daughter | 1 | Chr18(GRCh37):g.33736538G>A, NM_001242875.2(ELP2):c.1580G>A, p.(Arg527Gln) | Mental retardation, autosomal recessive 58 (OMIM 616054) |
| 9 | Turkey | Distant | One daughter with epilepsy and intellectual disability, no diagnosis, died at age 10 months | 1 | Chr12(GRCh37):g.56398257G>A, NM_000456.2(SUOX):c.1084G>A, p.(Gly362Ser) | Sulfite oxidase deficiency (OMIM 272300) |
| 10 | Palestine | 1st cousins | One deceased daughter homozygous for SLC26A2 variant | 1 | Chr5(GRCh37):g.149360962_149360965del, NM_000112.3(SLC26A2):c.1806_1809del, p.(Thr603Serfs*5) | Achondrogenesis type 1B (OMIM 600972) |
| 11 | Netherlands | Distant | One son homozygous for SGSH variant | 1 | Chr17(GRCh37):g.78187614C>T, NM_000199.4(SGSH):c.734G>A, p.(Arg245His) | Mucopolysaccharidosis type IIIA (Sanfilippo type A) (OMIM 605270) |
| 14 | Pakistan | 1st cousins | One daughter homozygous for HBB variant | 1 | Chr11(GRCh37):g.5247976_5247979dup, NM_000518.4(HBB):c.143_146dup, p.(Thr51Valfs*4) | β-thalassemia (OMIM 613985) |
| 16 | Netherlands | Distant | One son homozygous for GAA variant; multiple miscarriages; 10 weeks pregnant at inclusion | 2 |
Chr17(GRCh37):g.78082327A>T, NM_000152.3(GAA):c.1115A>T, p.(His372Leu) Chr1(GRCh37):g.40756551dup, NM_005857.4(ZMPSTE24):c.1085dup, p.(Leu362Phefs*19) |
Glycogen storage disease II (Pompe disease) (OMIM 232300) Lethal restrictive dermopathy (OMIM 275210) |
| 21 | Netherlands | Distant | One deceased son homozygous for SFTPB variant; one healthy daughter, one miscarriage | 1 | Chr2(GRCh37):g.85893772delinsTTC, NM_000542.3(SFTPB):c.397delinsGAA, p.(Pro133Glufs*95) | Pulmonary surfactant metabolism dysfunction 1 (OMIM 265120) |
| 22 | Turkey | 1st cousins | One deceased son homozygous for HEXB variant, one healthy daughter | 3 |
Chr2(GRCh37):g.1507755del, NM_000547.5(TPO):c.2422del, p.(Cys808Alafs*24) Chr15(GRCh37):g.83328380_83328383del, NM_001278512.1(AP3B2):c.3235_3238del, p.(Thr1079Serfs*7) Chr5(GRCh37):g.74016587_74016590dup, NG_009770.2(HEXB):c.1613 + 15_1613 + 18dup |
Thyroid dyshormonogenesis 2A (OMIM 274500) Early infantile epileptic encephalopathy 48 (OMIM 617276) Sandhoff disease (OMIM 268800) |
| 28 | Morocco | Distant | One daughter homozygous for OBSL1 variant | 1 | Chr2(GRCh37):g.220432786dup, NM_015311.2(OBSL1):c.1273dup, p.(Thr425Asnfs*40) | 3M syndrome (OMIM 612921) |
| 31 | Afghanistan | 1st cousins | Three healthy children, one IUD at 18 weeks | 1 | Chr22(GRCh37):g.24896073A>G, NG_012858.2(UPB1):c.105-2A>G | β-ureidopropionase deficiency (OMIM 613161) |
| 32 | Turkey | 1st cousins | One son homozygous for ACADVL variant, one healthy son | 1 | Chr17(GRCh37):g.7127050G>A, NG_007975.1(ACADVL):c.1269 + 1G>A | VLCAD deficiency (OMIM 201475) |
| 33 | Syria | 1st cousins | Two sons homozygous for C12orf57 variant | 1 | Chr12(GRCh37):g.7053285A>G, NM_138425.3(C12orf57):c.1A>G | Temtamy syndrome (OMIM 218340) |
| 36 | Morocco | 1st cousins | One son homozygous for MBOAT7 variant, one healthy daughter | 1 | Chr12(GRCh37):g.7053285A>G, NM_024298.4(MBOAT7):c.458_459del, p.(Leu153Glnfs*142) | Mental retardation, autosomal recessive 57 (OMIM 617188) |
| 37 | Palestine | 1st cousins | One son with congenital deafness | 1 | Chr7(GRCh37):g.87041333C>T, NM_000443.3(ABCB4):c.2800G>A, p.(Ala934Thr) | Gallbladder disease 1 (LPAC) (OMIM 600803) |
| 38 | Netherlands | 2nd cousins | Son homozygous for BLM variant | 1 | Chr15(GRCh37):g.91328183C>T, NM_000057.3(BLM):c.2695C>T, p.(Arg899*) | Bloom syndrome (OMIM 210900) |
| 43 | Afghanistan | 1st cousins | One deceased daughter with a skeletal dysplasia, diagnosis unknown | 1 | Chr14(GRCh37):g.92480711_92480714del, NM_004239.4(TRIP11):c.1031_1034del, p.(Arg344Lysfs*2) | Achondrogenesis, type IA (OMIM 200600) |
| 44 | Netherlands | Distant | One daughter with homozygous MRPL44 variant | 1 | Chr2(GRCh37):g.224824538T>G, NM_022915.3(MRPL44):c.467T>G, p.(Leu156Arg) | Combined oxidative phosphorylation deficiency 16 (OMIM 615395) |
| 45 | Syria | 1st cousins | One son homozygous for SMN1 ex7–8 deletion | 1 | NM_000344.3(SMN1): ex7-8del | Spinal muscular atrophy 1 (OMIM 253300) |
| 47 | Morocco | 2nd cousins | One daughter homozygous for TGM1 variant | 1 | Chr14(GRCh37):g.24728366del, NM_000359.2(TGM1):c.1074del, p.(Ser358Argfs*26) | Ichthyosis, congenital, autosomal recessive 1 (OMIM 242300) |
| 51 | Turkey | Double 1st cousins | One daughter homozygous for SCAPER variant | 2 |
Chr15(GRCh37):g.77057949_77057952del, NM_020843.3(SCAPER):c.1447_1450del, p.(Phe483Valfs*30) Chr7(GRCh37):g.87041275G>T, NM_000443.3(ABCB4):c.2858C>A, p.(Ala953Asp) |
Intellectual developmental disorder and retinitis pigmentosa (OMIM 618195) Cholestasis, progressive familial intrahepatic 3 (OMIM 602347) |
| 52 | Turkey | 1st cousins | One son, one daughter homozygous for NEK9 variant, one healthy daughter | 1 | Chr14(GRCh37):g.75576537G>A, NM_033116.5(NEK9):c.1033C>T, p.(Arg345*) | Lethal congenital contracture syndrome 10 (OMIM 617022) |
| 53 | Yemen/Sudan | 2nd cousins | One deceased daughter homozygous for WDR73 and IGHMBP2 variants | 3 |
Chr11(GRCh37):g.68696686G>T, NM_002180.2(IGHMBP2):c.1096G>T, p.(Glu366*) Chr15(GRCh37):g.85186706del, NM_032856.3(WDR73):c.1132del, p.(Arg378Alafs*25) Chr11(GRCh37):g.102991434C>T, NM_001080463.1(DYNC2H1):c.1151C>T, p.(Ala384Val) |
Charcot–Marie–Tooth disease, axonal, type 2S (OMIM 616155) Galloway–Mowat syndrome 1 (OMIM 251300) Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM 603297) |
| 54 | Pakistan | 3rd cousins | Two deceased sons homozygous for VIPAS39 variant | 1 | Chr14(GRCh37):g.77910630del, NM_001193314.1(VIPAS39):c.559del, p.(Glu187Argfs*3) | Arthrogryposis, renal dysfunction, and cholestasis 2 (ARCS2) (OMIM 613404) |
| 56 | Syria | 1st cousins | One deceased daughter, died at 3 years, progressive deterioration of hearing, seeing, epilepsy, no clinical diagnosis | 1 | Chr2(GRCh37):g.242683170del, NM_152783.4(D2HGDH):c.624del, p.(Gly209Glufs*31) | D-2-hydroxyglutaric aciduria (OMIM 600721) |
| 61 | Syria | 1st cousins | Son homozygous for HBB variant | 1 | Chr11(GRCh37):g.5248232T>A, NM_000518.4(HBB):c.20A>T, p.(Glu7Val) | Sickle cell anemia (OMIM 603903) |
| 62 | Turkey | 1st cousins | Son and daughter homozygous for MRTFA variant | 1 | Chr22(GRCh37):g.40815086dup, NM_020831.4(MRTFA):c.1356dup | Immunodeficiency 66 (OMIM 618847) |
| 63 | Syria | 1st/2nd cousins | Son with Sjogren–Larsson syndrome (arr 17p11.2(19,447,016-19,655,447)x0, one healthy daughter | 2ϯ |
Chr6(GRCh37):g.51609303A>G, NM_138694.3(PKHD1):c.10036T>C, p.(Cys3346Arg) maternal Chr6(GRCh37):g.51484077G>C, NM_138694.3(PKHD1):c.12027C>G, p.(Tyr4009*) paternal both carry (arr 17p11.2(19,447,016-19,655,447)x1 |
Polycystic kidney disease 4, with or without hepatic disease (OMIM 263200) Sjogren–Larsson syndrome |
| 65 | Afghanistan | 1st cousins | Two children homozygous for TCIRG1 variant | 1 | Chr11(GRCh37):g.67811762dup, NM_006019.3(TCIRG1):c.971dup, p.(Cys324Trpfs*166) | Osteopetrosis, autosomal recessive 1 (OMIM 259700) |
| 66 | Iraq | 1st cousins | 2ϯ |
Chr16(GRCh37):g.3293447C>G, NM_000243.2(MEFV):c.2040G>C, p.(Met680Ile), paternal Chr16(GRCh37):g.3293407T>C, NM_000243.2(MEFV):c.2080A>G, p.(Met694Val), maternal |
Familial Mediterranean fever, AR (OMIM 249100) | |
| 70 | Netherlands | 3rd cousins | One child homozygous for GJB2 variant | 1 | Chr13(GRCh37):g.20763686del, NM_004004.5(GJB2):c.35del, p.(Gly12Valfs*2) | Deafness, autosomal recessive 1A (OMIM 220290) |
| 71 | Turkey | 1st cousins | One son homozygous for PLA2G6 variant, one healthy daughter | 2 |
Chr22(GRCh37):g.38536033dup, NM_003560.3(PLA2G6):c.753dup, p.(Asn252Glnfs*130) Chr1(GRCh37):g.152281672del, NM_002016.1(FLG):c.5690del, p.(His1897Profs*198) |
Infantile neuroaxonal dystrophy 1 (OMIM 256600)/neurodegeneration with brain iron accumulation 2B (OMIM 610217) Ichthyosis vulgaris (OMIM 146700) |
| 72 | Netherlands | 1st cousins | 1 | Chr3(GRCh37):g.171431702G>A, NM_002662.4(PLD1):c.892C>T, p.(Arg298*) | Cardiac valvular defect, developmental (OMIM 212093) | |
| 75 | Unknown | 1st cousins | Seven spontaneous abortions, one healthy son | 1 | Chr12(GRCh37):g.110029107G>A, NM_000431.3(MVK):c.830G>A, p.(Arg277His) | Hyper-IgD syndrome (OMIM 260920) |
| 76 | Netherlands | 1st cousins | Deceased daughter homozygous for CLPB variant, one IUD at 16 weeks, one miscarriage; 7 weeks pregnant at inclusion | 2 |
Chr11(GRCh37):g.72005169G>A, NM_030813.5(CLPB):c.1772C>T, p.(Ala591Val) Chr16(GRCh37):g.84203896C>T, NM_178452.5(DNAAF1):c.1462C>T, p.(Arg488*) |
3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia (OMIM 616271) Ciliary dyskinesia, primary, 13 (OMIM613193) |
| 77 | Morocco | 1st cousins | One healthy daughter | 1 | Chr11(GRCh37):g.93523799_93523800del, NM_004268.4(MED17):c.477_478del, p.(Leu160Ilefs*9) | Microcephaly, postnatal progressive, with seizures and brain atrophy (OMIM 613668) |
| 78 | Afghanistan | 1st cousins | One termination of pregnancy homozygous for WNT10B and PKP1 variants | 2 |
Chr12(GRCh37):g.49360307del, NM_003394.3(WNT10B):c.741del, p.(Cys247*) Chr1(GRCh37):g.201288984C>T, NM_000299.3(PKP1):c.1273C>T, p.(Gln425*) |
Split-hand/foot malformation 6 (OMIM 225300) Ectodermal dysplasia/skin fragility syndrome (OMIM 604536) |
| 80 | Morocco | Distant | One daughter with ID and epilepsy | 1 | Chr15(GRCh37):g.28171357_28171358del, NM_000275.2(OCA2):c.1994_1995del, p.(Ala665Glyfs*4) | Albinism, oculocutaneous, type II (OMIM 203200) |
| 81 | Morocco | 1st cousins | One healthy daughter, one son homozygous for SLC13A5 variant | 1 | Chr17(GRCh37):g.6597517C>T, NG_034220.1(SLC13A5):c.1056-1G>A, p.? | Epileptic encephalopathy, early infantile, 25 (OMIM 615905) |
| 82 | Netherlands | 1st cousins | One deceased daughter homozygous for MYL2 variant | 2 |
Chr12(GRCh37):g.111348980C>G, NG_007554.1(MYL2):c.403-1G>C, p.? Chr11(GRCh37):g.68707139T>G, NM_002180.2(IGHMBP2):c.2922T>G, p.(Asp974Glu) |
Cardiomyopathy, hypertrophic, 10 (OMIM 608758) Spinal muscular atrophy with respiratory distress (OMIM 604320) |
| 83 | Syria | 1st cousins | One son homozygous for GUCY2D variant | 1 | Chr17(GRCh37):g.7917237G>A, NM_000180.3(GUCY2D):c.2303G>A, p.(Arg768Gln) | Leber congenital amaurosis 1 (OMIM 204000) |
| 84 | Afghanistan | 1st cousins | Three healthy children, 2 deceased sons homozygous for CEP290 variant | 1 | Chr12(GRCh37):g.88513990_88513994del, NM_025114.3(CEP290):c.1419_1423del, p.(Ile474Argfs*5) | Leber congenital amaurosis 10 (OMIM 611755) |
| 85 | Turkey | 1st cousins | Two deceased children homozygous for RMND1 variant, one living daughter homozygous for RMND1 variant and one healthy son | 2 |
Chr6(GRCh37):g.151738437G>C, NM_017909.3(RMND1):c.1177C>G, p.(Leu393Val) Chr2(GRCh37):g.152471058A>G, NM_001164507.1(NEB):c.11333T>C, p.(Ile3778Thr) |
Combined oxidative phosphorylation deficiency 11 (OMIM 614922) Nemaline myopathy 2, autosomal recessive (OMIM 256030) |
| 86 | Afghanistan | 1st cousins | Two deceased daughters homozygous for ERCC6 variant | 3 |
Chr10(GRCh37):g.50691430G>A, NM_000124.3(ERCC6):c.1954C>T, p.(Arg652*) Chr3(GRCh37):g.48929490G>A, NM_000387.5(SLC25A20):c.121C>T, p.(Gln41*) Chr8(GRCh37):g.105441818C>T, NM_001385.2(DPYS):c.905G>A, p.(Arg302Gln) |
Cockayne syndrome, type B (OMIM 133540) Carnitine-acylcarnitine translocase deficiency (OMIM 212138) Dihydropyrimidinuria (OMIM 222748) |
| 88 | Turkey | 1st cousins | One healthy daughter, one son homozygous for HBB variant | 2 |
Chr11(GRCh37):g.5248178_5248184del, NM_000518.4(HBB):c.68_74del, p.(Glu23Valfs*37) Chr19(GRCh37):g.45856060G>A, NM_000400.3(ERCC2):c.1846C>T, p.(Arg616Trp) |
β-thalassemia (OMIM 613985) Xeroderma pigmentosum, group D (OMIM 278730) |
| 90 | Netherlands | 1st cousins | 1 | Chr14(GRCh37):g.88452941T>C, NM_000153.3(GALC):c.334A>G, p.(Thr112Ala) | Krabbe disease (OMIM 245200) | |
| 92 | Iraq | 1st cousins | One daughter homozygous for CTNS variant; 9 weeks pregnant at inclusion | 1 | Chr17(GRCh37):g.3563574G>A, NM_001031681.2(CTNS):c.1015G>A, p.(Gly339Arg) | Cystinosis, nephropathic (OMIM 219800) |
| 93 | Turkey | 1st cousins | One healthy daughter, one deceased son homozygous for ALPL variant | 1 | Chr1(GRCh37):g.21889687G>A, NM_000478.5(ALPL):c.382G>A, p.(Val128Met) | Hypophosphatasia, infantile (OMIM 241500) |
| 94 | Morocco | 1st cousins | Four sons, two healthy, two termination of pregnancy due to hydrops fetalis | 1 | Chr17(GRCh37):g.18023748C>T, NM_016239.3(MYO15A):c.1634C>T, p.(Ala545Val) | Deafness, autosomal recessive 3 (OMIM 600316) |
| 95 | Morocco | Distant | One son homozygous for CHKB variant | 1 | Chr22(GRCh37):g.51018188dup, NM_005198.4(CHKB):c.999dup, p.(Leu334Thrfs*95) | Muscular dystrophy, congenital, megaconial type (OMIM 602541) |
| 96 | Turkey | 1st cousins | 8 weeks pregnant at inclusion | 1 | Chr11(GRCh37):g.17598421C>A, NM_001277269.1(OTOG):c.2604C>A, p.(Cys868*) | Deafness, autosomal recessive 18B (OMIM 614945) |
| 97 | Afghanistan | 1st/3rd cousins | One daughter homozygous for TH variant | 1 | Chr11(GRCh37):g.2185575G>A, NM_199292.2(TH):c.1475C>T, p.(Pro492Leu) | Segawa syndrome, recessive (OMIM 605407) |
| 100 | Iraq | 1st cousins | One deceased daughter due to hydrocephalus, diagnosis unknown | 1 | Chr14(GRCh37):g.91739503dup, NM_001080414.3(CCDC88C):c.5553dup, p.(Ser1852Glnfs*4) | Hydrocephalus, congenital, 1 (OMIM 236600) |
In bold: newly identified (novel) variants, in red: variants not (initially) identified by the current bioinformatics pipeline. ϯ indicates detection of compound heterozygous variants in the couple.
AR autosomal recessive, ID intellectual disability, IUD intrauterine death.