Table 1.
Identified pathogenic mutations in six established AOS genes
| Fam ID | Gene | Zygosity | Nucleotide changea | Amino acid change | Type of mutation | Pathogenicity class | Mutation previously reported | Reference of familyb |
|---|---|---|---|---|---|---|---|---|
| Pedigrees suggestive of autosomal recessive inheritance: | ||||||||
| 4 | DOCK6 | Homozygous | c.484G > T | p.Glu162* | Nonsense | Pathogenic | c | Sukalo et al., 2015 (Family 8) |
| 6 | DOCK6 | Homozygous | c.1296_1297delinsT | p.Gln434Argfs*21 | Frameshift | Pathogenic | c | Sukalo et al., 2015 (Family 3) |
| 8 | DOCK6 | Homozygous | c.2520dupT | p.Arg841Serfs*6 | Frameshift | Pathogenic | c, d | Sukalo et al., 2015 (Family 10) |
| 9 | DOCK6 | Homozygous | c.3047T > C | p.Leu1016Pro | Missense | Likely pathogenic | c | Sukalo et al., 2015 (Family 1) |
| 10 | DOCK6 | Homozygous | c.3154G > A | p.Glu1052Lys | Missense | Likely pathogenic | c | Sukalo et al., 2015 (Family 5); Prothero et al., 2007 |
| 11 | DOCK6 | Homozygous | c.4786C > T | p.Arg1596Trp | Missense | Likely pathogenic | c | Sukalo et al., 2015 (Family 4) |
| 13 | DOCK6 | Homozygous | c.5235+205_6102‐15delinsCATGGGGCTG | 4.3 kb deletion | Deletion | Pathogenic | c | Sukalo et al., 2015 (Family 9) |
| 5 | DOCK6 | Compound heterozygous | c.788T > A | p.Val263Asp | Missense | Likely pathogenic | c | Sukalo et al., 2015 (Family 6); Orstavik et al., 1995 |
| c.5939+2T > C | p.? | Splicing | Pathogenic | |||||
| 7 | DOCK6 | Compound heterozygous | c.1902_1905delGTTC | p.Phe635Profs*32 | Frameshift | Pathogenic | c | Sukalo et al., 2015 (Family 7) |
| c.4106+5G > T | p.? | Splicing | Likely pathogenic | |||||
| 1 | EOGT | Homozygous | c.311+1G > T | p.? | Splicing | Pathogenic | Novel mutation | ‐ |
| 2 | EOGT | Homozygous | c.404G > A | p.Cys135Tyr | Missense | Pathogenic | Novel mutation | ‐ |
| 3 | EOGT | Homozygous | c.1130G > A | p.Arg377Gln | Missense | Likely pathogenic | d | Temtamy et al., 2007 (Family 2) |
| 59 | EOGT | Compound heterozygous | c.78_81delTCAC | p.His27Alafs*46 | Frameshift | Pathogenic | Novel mutation | Verdyck et al., 2003 (Family 4) |
| c.1335‐1G > A | p.? | Splicing | Pathogenic | Novel mutation | ||||
| Pedigrees suggestive of autosomal dominant inheritance: | ||||||||
| 40 | ARHGAP31 | Heterozygous | c.2047C > T | p.Gln683* | Nonsense | Pathogenic | c | Southgate et al., 2011 (Family AOS‐12); Bonafede & Beighton, 1979 |
| 41 | ARHGAP31 | Heterozygous | c.2047C > T | p.Gln683* | Nonsense | Pathogenic | d | ‐ |
| 42 | ARHGAP31 | Heterozygous | c.2063_2064insTT | p.Ser689* | Nonsense | Pathogenic | c | Isrie et al., 2014 |
| 43 | ARHGAP31 | Heterozygous | c.3260delA | p.Lys1087Serfs*4 | Frameshift | Pathogenic | c | Southgate et al., 2011 (Family AOS‐5); Verdyck et al., 2006 |
| 55 | DLL4 | Heterozygous | c.556C > T | p.Arg186Cys | Missense | Likely pathogenic | c | Meester et al., 2015 (Family 6) |
| 56 | DLL4 | Heterozygous | c.1168T > C | p.Cys390Arg | Missense | Pathogenic | c | Meester et al., 2015 (Family 5) |
| 57 | DLL4 | Heterozygous | c.1365C > G | p.Cys455Trp | Missense | Pathogenic | c | Meester et al., 2015 (Family 3) |
| 58 | DLL4 | Heterozygous | c.1660C > T | p.Gln554* | Nonsense | Pathogenic | c | Meester et al., 2015 (Family 1) |
| 181 | DLL4 | Heterozygous | c.1825C > T | p.Gln609* | Nonsense | Pathogenic | Novel mutation; de novo | ‐ |
| 14 | NOTCH1 | Heterozygous | c.415C > T | p.Gln139* | Nonsense | Pathogenic | Novel mutation | ‐ |
| 46 | NOTCH1 | Heterozygous | c.794_797delinsCC | p.Asn265Thrfs*65 | Frameshift | Pathogenic | Novel mutation | ‐ |
| 47 | NOTCH1 | Heterozygous | c.1649dupA | p.Tyr550* | Nonsense | Pathogenic | c | Southgate et al., 2015 (Family 1), Verdyck et al., 2003 (Family 2) |
| 48 | NOTCH1 | Heterozygous | c.1935_1936delTG | p.Ala646Glnfs*21 | Frameshift | Pathogenic | Novel mutation | Savarirayan et al., 1999 |
| 50 | NOTCH1 | Heterozygous | c.4120T > C | p.Cys1374Arg | Missense | Pathogenic | c | Southgate et al., 2015 (Family 3) |
| 52 | NOTCH1 | Heterozygous | c.4663G > T | p.Glu1555* | Nonsense | Pathogenic | c | Southgate et al., 2015 (Family 4) |
| 54 | NOTCH1 | Heterozygous | c.6049_6050delTC | p.Ser2017Thrfs*9 | Frameshift | Pathogenic | c | Southgate et al., 2015 (Family 2); Dallapiccola et al. 1992 (Patient 2) |
| 44 | RBPJ | Heterozygous | c.193A > G | p.Arg65Gly | Missense | Likely pathogenic | Novel mutation | ‐ |
| 175 | RBPJ | Heterozygous | c.196T > G | p.Phe66Val | Missense | Likely pathogenic | Novel mutation | ‐ |
| 45 | RBPJ | Heterozygous | c.505A > G | p.Lys169Glu | Missense | Pathogenic | d | ‐ |
| 178 | RBPJ | Heterozygous | c.996C > A | p.Ser332Arg | Missense | Likely pathogenic | Novel mutation | ‐ |
| Sporadic probands: | ||||||||
| 17 | ARHGAP31 | Heterozygous | c.2047C > T | p.Gln683* | Nonsense | Pathogenic | d | ‐ |
| 18 | ARHGAP31 | Heterozygous | c.2182C > T | p.Gln728* | Nonsense | Pathogenic | Novel mutation | ‐ |
| 30 | DLL4 | Heterozygous | c.361G > C | p.Ala121Pro | Missense | Likely pathogenic | c; de novo | Meester et al., 2015 (Family 8) |
| 31 | DLL4 | Heterozygous | c.572G > A | p.Arg191His | Missense | Likely pathogenic | d | ‐ |
| 32 | DLL4 | Heterozygous | c.583T > C | p.Phe195Leu | Missense | Likely pathogenic | c | Meester et al., 2015 (Family 9) |
| 182 | DLL4 | Heterozygous | c.949A > C | p.Thr317Pro | Missense | Likely pathogenic | Novel mutation; de novo | ‐ |
| 34 | DLL4 | Heterozygous | c.1169G > A | p.Cys390Tyr | Missense | Pathogenic | c | Meester et al., 2015 (Family 4) |
| 196 | DLL4 | Heterozygous | c.1310G > C | p.Cys437Ser | Missense | Pathogenic | Novel mutation | ‐ |
| 35 | DLL4 | Heterozygous | c.1397G > A | p.Cys466Tyr | Missense | Pathogenic | Novel mutation; de novo | ‐ |
| 36 | DOCK6 | Compound heterozygous | c.484G > T | p.Glu162* | Nonsense | Pathogenic | d | Romani et al., 1998 |
| c.1362_1365delAACT | p.Thr455Serfs*24 | Frameshift | Pathogenic | d, d | ||||
| 37 | DOCK6 | Compound heterozygous | c.1362_1365delAACT | p.Thr455Serfs*24 | Frameshift | Pathogenic | c, d | Sukalo et al., 2015 (Family 2) |
| c.4491+1G > A | p.? | Splicing | Pathogenic | c | ||||
| 38 | EOGT | Homozygous | c.78_81delTCAC | p.His27Alafs*46 | Frameshift | Pathogenic | Novel mutation | ‐ |
| 39 | EOGT | Homozygous | c.78_81delTCAC | p.His27Alafs*46 | Frameshift | Pathogenic | Novel mutation | ‐ |
| 22 | NOTCH1 | Heterozygous | c.1343G > A | p.Arg448Gln | Missense | Pathogenic | c; de novo | Southgate et al., 2015 (Family 5) |
| 23 | NOTCH1 | Heterozygous | c.1343G > A | p.Arg448Gln | Missense | Pathogenic | c | Southgate et al., 2015 (Family 11); Girard et al., 2005 (Patient 2) |
| 24 | NOTCH1 | Heterozygous | c.1345T > C | p.Cys449Arg | Missense | Pathogenic | c; de novo | Southgate et al., 2015 (Family 6) |
| 25 | NOTCH1 | Heterozygous | c.1367G > A | p.Cys456Tyr | Missense | Pathogenic | c; de novo | Southgate et al., 2015 (Family 10); Girard et al., 2005 (Patient 1) |
| 21 | NOTCH1 | Heterozygous | c.1393G > A | p.Ala465Thr | Missense | Likely pathogenic | Novel mutation | ‐ |
| 26 | NOTCH1 | Heterozygous | c.1669+5G > A | p.? | Splicing e | Pathogenic | Novel mutation | ‐ |
| 27 | NOTCH1 | Heterozygous | c.2380G > T | p.Glu794* | Nonsense | Pathogenic | Novel mutation | ‐ |
| 15 | NOTCH1 | Heterozygous | c.2704C > T | p.Arg902Cys | Missense | Pathogenic | Novel mutation | ‐ |
| 49 | NOTCH1 | Heterozygous | c.3281G > A | p.Cys1094Tyr | Missense | Pathogenic | Novel mutation | ‐ |
| 198 | NOTCH1 | Heterozygous | c.4222G > T | p.Glu1408* | Nonsense | Pathogenic | Novel mutation; de novo | ‐ |
| 183 | NOTCH1 | Heterozygous | c.4549G > A | p.Asp1517Asn | Missense | Likely pathogenic | Novel mutation; de novo | Verdyck et al., 2003 (Family 8) |
| 28 | NOTCH1 | Heterozygous | c.4739dup | p.Met1580Ilefs*30 | Frameshift | Pathogenic | c | Southgate et al., 2015 (Family 8) |
a
GenBank reference sequence and version number for ARHGAP31: NM_020754.3; DLL4: NM_019074.3; DOCK6: NM_020812.3; EOGT: NM_001278689.1; NOTCH1: NM_017617.4; RBPJ: NM_005349.3; numbering is from +1 as A of the ATG initiation codon.
b
This column refers to medical case reports in which clinical features observed in specific families are described.
c
Mutation was found in the same family as described in this publication.
d
Mutation published previously in a different family.
e
Exon skipping was verified at the RNA level.