Disease-associated variants in the human genome are continually being identified using DNA sequencing technologies that are especially effective for Mendelian disorders. Here we sequenced whole genome to high coverage (>30×) of 6 members of a 7-generation family with dwarfism from a consanguineous tribe in Pakistan to determine the causal variant(s). We identified a missense variant rs111033552 (c.2011T>C [p.Ser671Pro]) located in COL10A1 (encodes the alpha chain of type X collagen) as the most likely contributor to the dwarfism. We further confirmed the variant in 22 family members using Sanger sequencing. All affected individuals are heterozygous for the missense mutation rs111033552 and no individual homozygous was observed. Moreover, the mutation was absent in 69,985 individuals representing >150 global populations. Taking advantage of whole-genome sequencing data, we also examined other variant forms, including copy number variation and insertion/deletion, but failed to identify such variants enriched in the affected individuals. Thus rs111033552 had priority for linkage with dwarfism.
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C Zhang and J Liu contributed equally to this work.
SX acknowledges financial support from the Strategic Priority Research Program (XDB13040100) and Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) of the Chinese Academy of Sciences (CAS), the National Natural Science Foundation of China (NSFC) grant (91331204, 91731303, 31771388, and 31711530221), the National Science Fund for Distinguished Young Scholars (31525014), the Program of Shanghai Academic Research Leader (16XD1404700), and the National Key Research and Development Program (2016YFC0906403); YL acknowledges support from NSFC grant (31501011) and Science and Technology Commission of Shanghai Municipality (STCSM) (14YF1406800); HL acknowledges support from NSFC grant (31601046) and STCSM grant (16YF1413900); SX is a Max-Planck Independent Research Group Leader and member of CAS Youth Innovation Promotion Association. SX also gratefully acknowledges the support of the National Program for Top-notch Young Innovative Talents of the “Wanren Jihua” Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank LetPub (www.letpub.com) and Dr Asifullah Khan for their linguistic assistance during the preparation of this manuscript.
S.X. conceived and designed the study and supervised the project. F.I., M.A., F.B., and I.B., contributed to sample and phenotype collection. Y.L. managed laboratory work. S.X. contributed reagents and materials. C.Z. developed pipeline for processing NGS data and performed variant calling analysis. H.L., R.F., and Z. W developed pipeline for structural variation analysis. C.Z. and J.L. analyzed the data. S.X., and C.Z. wrote the main paper. C.Z. and J.L. prepared the Supplementary Information. All authors discussed the results and implications and commented on the manuscript.