Molecular diagnosis and clinical presentations of individuals with FANCB pathogenic variants
| . | Individual . | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1* . | 2* . | 3 . | 4 . | 5 . | 6 . | 7 . | 8 . | 98 . | 1020 . | 11† . | 12† . | 13 . | 14 . | 15 . | 16 . | 17‡ . | 18‡ . | 19 . | 20 . | 2121 . | |
| FANCB variant (hg19) | g.14547941-15137983§ | g.14547941-15137983§ | g.14430386-14950531§ | g.14868626 | g.14862864 | g.14862731 | g.14882684 | g.14877305 | g.14862640 | g.14878137-14887099 | g.14862094-14862097 | g.14862094-14862097 | g.14883438 | g.14863091-14863094 | g.14862020; g.14862017-14862020 | g.14883505 | g.14877422 | g.14877422 | g.14868688 | g.14862763 | g.14883380 |
| FANCB variant (NM_001018113) | WGD | WGD | WGD | c.1496+1G>A p.K443Vfs*4 | c.1928-2A>T | c.2059G>T p.E687* | c.949C>T p.Q317*; p.G294Cfs*3‖ | c.1103C>A p.S368* | c.2150T>G p.L717* | c.-155_952-470dup p.A319* | c.2172_2175delAACA p.T725Lfs*15 | c.2172_2175delAACA p.T725Lfs*15 | c.195dupT p.F65Vfs*8 | c.1811_1814delGAGA p.R604Kfs*18 | c.2249G>T p.G750V¶; c.2249_2252delGAAG p.G750Vfs*5 | c.128T>C p.L43S | c.986T>C p.L329P | c.986T>C p.L329P | c.1435T>G p.W479G, p.K443Vfs*4‖ | c.2027T>C p.L676P | c.353T>C p.F118S |
| Variant type | Large deletion | Large deletion | Large deletion | Splicing defect | Splicing defect? | Nonsense | Nonsense | Nonsense | Nonsense | Duplication | Indel | Indel | Indel | Indel | Missense and indel | Missense | Missense | Missense | Missense | Missense | Missense |
| Origin | Inherited | Inherited | Inherited | ND | ND | Inherited | Inherited | Inherited | ND | Inherited | Inherited | Inherited | Inherited | De novo | De novo | De novo | Inherited | Inherited | ND | De novo | ND |
| Postnatal survival, mo | 0.5 | 29 | Alive (168) | 0.033 | Alive (168) | 136 | Medical abortion | Medical abortion | Medical abortion | Alive (168) | 1.1 | Medical abortion | 0.2 | Alive (132) | ND | 45 | 104 | 80 | 120 | Alive (108) | Alive (11 yrs) |
| Reason for death | MCA complications | MCA complications | NA | MCA complications | NA | AML | Medical abortion | Medical abortion | Medical abortion | NA | Surgery complication | Medical abortion | MCA complications | NA | ND | BMT complications | Infection | Infection | BMT complications | NA | NA |
| Abnormal heme onset, mo | — | — | 0.23 | — | 36 | 48 | NA | NA | NA | 132 (mosaic) | 0.46 | NA | — | 12 | ND | 12 | 43 | 18 | 26 | 72 | 104 |
| HSCT, mo | NA | NA | 60 | NA | 54 | None | NA | NA | NA | None | None | NA | NA | 84 | ND | 42 | None | None | 108 | 93 | 113 |
| Congenital anomalies | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, imperforate anus, microcephaly, hydrocephalus, atrioventricular canal defect, ASD, hypoplastic left ventricle, cryptorchidism, penile-scrotal fusion, bilateral microtia, aplastic kidney (R), bilateral absence of auditory canal, bilateral 2-3 toe syndactyly | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, abnormal kidneys, poor lung function, hypoplastic urethra, hypoplastic gonads, hydrocephalus | Left aplastic thumb, right hypoplasitic thumb, right supernumerary thumb, left aplastic radius, microcephaly, ASD, PDA, distal aortic arch hypoplasia, aortic valve abnormality, bilateral hypoplastic auditory canals, bilateral hearing loss | Bilateral aplastic thumbs, bilateral aplastic radii, imperforate anus, aplastic kidney (L), unspecified cardiac abnormalities, diaphragmatic hernia, anophthalmia | Esophageal atresia, tracheoesophageal fistula, intestinal malrotation, PDA, microcephaly, PFO, ectopic kidney (R), bilateral vesicoureteral reflux, cryptorchidism (L), hypospadias, café-au-lait spots, microstomia, bilateral microphthalmia | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, duodenal atresia, hydrocephalus, microcephaly, dysplastic kidney (R), micropenis, bilateral cryptorchidism, aplastic kidney (L), microtia (R), absence of auditory canal (R), hearing loss (R), café-au-lait spots | Bilateral aplastic thumbs, bilateral hypoplastic radii, left hypoplastic ulna, hydrocephaly, dysplastic kidney (R), ectopic kidney (R), single umbilical artery | Bilateral aplastic thumbs, bilateral hypoplastic radii, bilateral hypoplastic ulnae, esophageal atresia, duodenal atresia, macrocephaly, complex heart defects, bilateral ectopic kidneys, hyper/hypopigmentation of the skin, liver/pancreas/spleen abnormalities, lung hypoplasia, nephrocalcinosis | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, imperforate anus, ventriculomegaly, 2-3 finger syndactyly (R) | Tracheomalacia, café-au-lait spots, hyper/hypopigmentation of the skin | Bilateral aplastic thumbs, bilateral aplastic radii, sacrospinal anomaly, esophageal atresia, tracheoesophageal fistula, ectopic kidney (L), posterior urethral valves | Esophageal atresia, tracheoesophageal fistula, ectopic kidney (L) | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, duodenal atresia, imperforate anus, hydrocephalus, pulmonary atresia, bilateral hydronephrosis, bilateral cryptorchidism, micropenis, bilateral microphthalmia | Bilateral aplastic thumbs, bilateral hypoplastic radii, esophageal atresia, microcephaly, VSD, ASD, vesicoureteral reflux (L), bilateral microtia, café-au-lait spots, hyper/hypopigmentation of the skin, bilateral microphthalmia | ND | Bilateral aplastic thumbs, bilateral aplastic radii, tracheal ring, laryngo/bronchomalacia hydrocephalus, PPS, ectopic kidney (R), micropenis, bilateral hydronephrosis, hypospadias, bilateral hypoplastic auditory canals, bilateral hearing loss, café-au-lait spots | Micropenis, bilateral cryptorchidism, hypoplastic toe nails, widely spaced nipples | Café-au-lait spots, microphthalmia (L) | Bilateral clinodactyly of fifth, microcephaly | Bilateral aplastic thumbs, bilateral hypoplastic radii, tracheoesophageal fistula, imperforate anus, VSD, PDA, hydrocephalus, PPS, right sided aortic arch, bilateral ectopic kidneys, microtia (R), bilateral vesicoureteral reflex, hypospadias, absence of auditory canal (R), hearing loss (R) | Microcephaly, microphthalmia, triangular face, micrognathia, low set ears, hypoplastic radius, hypoplastic ulna |
| VACTERL-H# | ACTERL-H | TRL-H | CRL | ACRL | CTER | TRL-H | RL-H | CERL-H | ACTL | VTERL | TER | ATRL-H | CEL | ND | TRL-H | ACTRL-H | |||||
| VACTERL subtype** | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | NO-VACTERL | VACTERL-PLUS | VACTERL-PLUS | VACTERL-LIKE | VACTERL-LIKE | VACTERL-PLUS | VACTERL-PLUS | ND | VACTERL-PLUS | VACTERL-PLUS | |||||
| . | Individual . | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1* . | 2* . | 3 . | 4 . | 5 . | 6 . | 7 . | 8 . | 98 . | 1020 . | 11† . | 12† . | 13 . | 14 . | 15 . | 16 . | 17‡ . | 18‡ . | 19 . | 20 . | 2121 . | |
| FANCB variant (hg19) | g.14547941-15137983§ | g.14547941-15137983§ | g.14430386-14950531§ | g.14868626 | g.14862864 | g.14862731 | g.14882684 | g.14877305 | g.14862640 | g.14878137-14887099 | g.14862094-14862097 | g.14862094-14862097 | g.14883438 | g.14863091-14863094 | g.14862020; g.14862017-14862020 | g.14883505 | g.14877422 | g.14877422 | g.14868688 | g.14862763 | g.14883380 |
| FANCB variant (NM_001018113) | WGD | WGD | WGD | c.1496+1G>A p.K443Vfs*4 | c.1928-2A>T | c.2059G>T p.E687* | c.949C>T p.Q317*; p.G294Cfs*3‖ | c.1103C>A p.S368* | c.2150T>G p.L717* | c.-155_952-470dup p.A319* | c.2172_2175delAACA p.T725Lfs*15 | c.2172_2175delAACA p.T725Lfs*15 | c.195dupT p.F65Vfs*8 | c.1811_1814delGAGA p.R604Kfs*18 | c.2249G>T p.G750V¶; c.2249_2252delGAAG p.G750Vfs*5 | c.128T>C p.L43S | c.986T>C p.L329P | c.986T>C p.L329P | c.1435T>G p.W479G, p.K443Vfs*4‖ | c.2027T>C p.L676P | c.353T>C p.F118S |
| Variant type | Large deletion | Large deletion | Large deletion | Splicing defect | Splicing defect? | Nonsense | Nonsense | Nonsense | Nonsense | Duplication | Indel | Indel | Indel | Indel | Missense and indel | Missense | Missense | Missense | Missense | Missense | Missense |
| Origin | Inherited | Inherited | Inherited | ND | ND | Inherited | Inherited | Inherited | ND | Inherited | Inherited | Inherited | Inherited | De novo | De novo | De novo | Inherited | Inherited | ND | De novo | ND |
| Postnatal survival, mo | 0.5 | 29 | Alive (168) | 0.033 | Alive (168) | 136 | Medical abortion | Medical abortion | Medical abortion | Alive (168) | 1.1 | Medical abortion | 0.2 | Alive (132) | ND | 45 | 104 | 80 | 120 | Alive (108) | Alive (11 yrs) |
| Reason for death | MCA complications | MCA complications | NA | MCA complications | NA | AML | Medical abortion | Medical abortion | Medical abortion | NA | Surgery complication | Medical abortion | MCA complications | NA | ND | BMT complications | Infection | Infection | BMT complications | NA | NA |
| Abnormal heme onset, mo | — | — | 0.23 | — | 36 | 48 | NA | NA | NA | 132 (mosaic) | 0.46 | NA | — | 12 | ND | 12 | 43 | 18 | 26 | 72 | 104 |
| HSCT, mo | NA | NA | 60 | NA | 54 | None | NA | NA | NA | None | None | NA | NA | 84 | ND | 42 | None | None | 108 | 93 | 113 |
| Congenital anomalies | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, imperforate anus, microcephaly, hydrocephalus, atrioventricular canal defect, ASD, hypoplastic left ventricle, cryptorchidism, penile-scrotal fusion, bilateral microtia, aplastic kidney (R), bilateral absence of auditory canal, bilateral 2-3 toe syndactyly | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, abnormal kidneys, poor lung function, hypoplastic urethra, hypoplastic gonads, hydrocephalus | Left aplastic thumb, right hypoplasitic thumb, right supernumerary thumb, left aplastic radius, microcephaly, ASD, PDA, distal aortic arch hypoplasia, aortic valve abnormality, bilateral hypoplastic auditory canals, bilateral hearing loss | Bilateral aplastic thumbs, bilateral aplastic radii, imperforate anus, aplastic kidney (L), unspecified cardiac abnormalities, diaphragmatic hernia, anophthalmia | Esophageal atresia, tracheoesophageal fistula, intestinal malrotation, PDA, microcephaly, PFO, ectopic kidney (R), bilateral vesicoureteral reflux, cryptorchidism (L), hypospadias, café-au-lait spots, microstomia, bilateral microphthalmia | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, duodenal atresia, hydrocephalus, microcephaly, dysplastic kidney (R), micropenis, bilateral cryptorchidism, aplastic kidney (L), microtia (R), absence of auditory canal (R), hearing loss (R), café-au-lait spots | Bilateral aplastic thumbs, bilateral hypoplastic radii, left hypoplastic ulna, hydrocephaly, dysplastic kidney (R), ectopic kidney (R), single umbilical artery | Bilateral aplastic thumbs, bilateral hypoplastic radii, bilateral hypoplastic ulnae, esophageal atresia, duodenal atresia, macrocephaly, complex heart defects, bilateral ectopic kidneys, hyper/hypopigmentation of the skin, liver/pancreas/spleen abnormalities, lung hypoplasia, nephrocalcinosis | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, imperforate anus, ventriculomegaly, 2-3 finger syndactyly (R) | Tracheomalacia, café-au-lait spots, hyper/hypopigmentation of the skin | Bilateral aplastic thumbs, bilateral aplastic radii, sacrospinal anomaly, esophageal atresia, tracheoesophageal fistula, ectopic kidney (L), posterior urethral valves | Esophageal atresia, tracheoesophageal fistula, ectopic kidney (L) | Bilateral aplastic thumbs, bilateral aplastic radii, tracheoesophageal fistula, duodenal atresia, imperforate anus, hydrocephalus, pulmonary atresia, bilateral hydronephrosis, bilateral cryptorchidism, micropenis, bilateral microphthalmia | Bilateral aplastic thumbs, bilateral hypoplastic radii, esophageal atresia, microcephaly, VSD, ASD, vesicoureteral reflux (L), bilateral microtia, café-au-lait spots, hyper/hypopigmentation of the skin, bilateral microphthalmia | ND | Bilateral aplastic thumbs, bilateral aplastic radii, tracheal ring, laryngo/bronchomalacia hydrocephalus, PPS, ectopic kidney (R), micropenis, bilateral hydronephrosis, hypospadias, bilateral hypoplastic auditory canals, bilateral hearing loss, café-au-lait spots | Micropenis, bilateral cryptorchidism, hypoplastic toe nails, widely spaced nipples | Café-au-lait spots, microphthalmia (L) | Bilateral clinodactyly of fifth, microcephaly | Bilateral aplastic thumbs, bilateral hypoplastic radii, tracheoesophageal fistula, imperforate anus, VSD, PDA, hydrocephalus, PPS, right sided aortic arch, bilateral ectopic kidneys, microtia (R), bilateral vesicoureteral reflex, hypospadias, absence of auditory canal (R), hearing loss (R) | Microcephaly, microphthalmia, triangular face, micrognathia, low set ears, hypoplastic radius, hypoplastic ulna |
| VACTERL-H# | ACTERL-H | TRL-H | CRL | ACRL | CTER | TRL-H | RL-H | CERL-H | ACTL | VTERL | TER | ATRL-H | CEL | ND | TRL-H | ACTRL-H | |||||
| VACTERL subtype** | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | VACTERL-PLUS | NO-VACTERL | VACTERL-PLUS | VACTERL-PLUS | VACTERL-LIKE | VACTERL-LIKE | VACTERL-PLUS | VACTERL-PLUS | ND | VACTERL-PLUS | VACTERL-PLUS | |||||
ASD, atrial septal defect; BMT, bone marrow transplantation; MCA, major congenital anomaly; NA, not applicable; ND, no data available; PDA, patent ductus arteriosus; PFO, patent foramen ovale; PPS, peripheral pulmonic stenosis; VSD, ventricular septal defect.
Sibling pair.
Sibling pair.
Sibling pair.
Based on 5 million single-nucleotide polymorphism chip data.
Cryptic splice variant (refer to Figure 2).
Transcript unstable (refer to Figure 3 and supplemental Figure 3).
Designation as described.7,26
Designation as described27 (only for 15 individuals with VACTERL-H).