Identified DYNC2H1 mutations
| Family | Nucleotide change | Mutation | Var | Location | ID method | Remarks | Functional validation |
|---|---|---|---|---|---|---|---|
| JATD-1 | c. 90443A>G | p.D3015G | Het | Exon 57 | WES (Agilent 38 Mb) | rs137853027† | ∼50% of cilia have bulged tips filled with IFT-B proteins, normal cilia length. rs137853027: minor allele frequency (EVS) 3 in 11957 alleles (0.00026 or 0.026%) |
| c. 1306G>T | p.E436* | Het | Exon 9 | SS | |||
| JATD-2 | c.9044A>G | p.D3015G | Het | Exon 57 | WES (Agilent 38 Mb) | rs137853027† | ∼50% of cilia have bulged tips filled with IFT-B proteins, normal cilia length. rs137853027: Minor allele frequency (EVS) 3 in 11957 alleles (0.00026 or 0.026%) |
| c.3459-1G>A | Exon 24 splice acceptor | Het | Intron 23 | SS | |||
| JATD-3 | c.9817C>T | p.E3273* | Het | Exon 62 | WES (Agilent 50 Mb) | ∼ 15% of cilia have bulged tips filled with IFTB proteins, normal cilia length | |
| c.7442G>A | p.R2481Q | Het | Exon 46 | ||||
| JATD-4 | c.1306G>T | p.E436* | Het | Exon 9 | WES (Agilent 50 Mb) | ||
| c.8457A>G | p.I2819M | Het | Exon 53 | ||||
| JATD-5 | c.3682C>A | p.L1228I | Het | Exon 25 | WES (Nimblegen V.3) | rs189806840 (dbSNP) | rs137853027: Minor allele frequency (EVS) 16 in 11820 alleles (0.00135 or 0.135%) |
| c.7663G>A | p.V2555M | Het | Exon 47 | ||||
| c.7718A>G | p.Y2573C | Het | Exon 48 | ||||
| JATD-6 | 14kb deletion (g.103191405-103204921) | p.G3891_Q4020del | Het | Del exons 81–83 | SNP microarray CNV analysis and SS | ||
| c.9044A>G | p.D3015G | Het | Exon 57 | SS | rs137853027† | rs137853027: minor allele frequency (EVS) 3 in 11957 alleles (0.00026 or 0.026%) | |
| c.11437C>T | p.R3813C | Het | Exon 79 | SS | |||
| JATD-7 | c.10163C>T | p.P3388L | Het | Exon 67 | WES (Agilent 50 Mb) | ||
| c.12480_13556del (g.103325916-103350592) | p.N4160_Q4314del | Het | Del exons 87–90 | Exome CNV analysis | |||
| JATD-8 | c.3719T>C | p.I1240T | Het | Exon 25 | WES (Agilent 50 Mb) | rs137853028† | rs137853028: not seen in EVS |
| c.12716T>G | p.L4239R | Het | Exon 89 | ||||
| JATD-9 | c. 11560T>G | p.W3854G | Hom | Exon 80 | HZ mapping (250 K) then SS | ||
| JATD-10 | c.6910G>A | p.A2304T | Het | Exon 43 | SS | 3 affected sibs | |
| c.8389_8397delCCAGCTTTG | p.P2797_L2799del | Het | Exon 52 | WES (Agilent 50 Mb) | |||
| JATD-11 | c.195G>T | p.T65T | Het | Exon 1 splice donor | WES (Agilent 50 Mb) | ||
| c.4135A>G | p.M1379V | Het | Exon 27 | ||||
| JATD-12 | c.312_313delTA | p.P104PfsX*2 | Het | Exon 2 | WES (Agilent 50 Mb) | 3 affected sibs | |
| c.5972T>A | p.M1991K | Het | Exon 38 | ||||
| JATD-13 | c.4325G>A | p.G1442D | Het | Exon 28 | WES (Agilent 50 Mb) | ||
| c.1953G>A | p.K651K | Het | Exon 13 splice donor | ||||
| JATD-14 | c.988C>T | p.R330C | Hom | Exon 6 | WES (Agilent 50 Mb) | 2 affected sibs | |
| JATD-15 | c. 7594C>T | p.R2532W | Hom | Exon 47 | WES (Agilent 50 Mb) | ||
| JATD-16 | c.7437+3A>G | Exon 45 splice donor | Het | Intron 45 | WES (Agilent 50 MB) | Normal cilia length | |
| c.7539A>T | p.G2513G | Het | Exon 46 splice donor | ||||
| JATD-17 | c.6679A>G | p.M2227V | Hom | Exon 42 | WES (Agilent 50 Mb) | ||
| c.12538delC | p.L4177Ffs*29 | Het | Exon 87 | ||||
| JATD-18 | c.2346-5T>G | Exon 17 splice acceptor | Het | Intron 16 | WES (Agilent 50 Mb) | 2 affected sibs | |
| c.7085A>G | p.N2362S | Het | Exon 43 | ||||
| JATD-19 | c.7919T>C | p.I2640T | Het | Exon 49 | WES (Agilent 50 Mb) | 2 affected sibs | |
| c.2612T>C | p.L871P | Het | Exon 18 |
†Annotated as pathogenic in dbSNP due to previous publication.13 EVS, NHLBI Exome Variant Server (http://evs.gs.washington.edu/EVS/). Functional validation refers to analysis in ciliated patient-derived fibroblasts. Nucleotides numbered according to Ensembl transcript DYNC2H1-005 ENST00000398093.
WES, whole exome sequencing with Agilent 38 or 50 Mb kit or Nimblegen V.3 kit; SS, Sanger sequencing; HZ mapping, SNP array-based homozygosity mapping.
CNV, copy number variation; IFT, intraflagellar transport; JATD, Jeune asphyxiating thoracic dystrophy; SNP, single nucleotide polymorphism.
*Indicates a stop codon insertion.