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A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus
Author(s) -
Loftus Stacie K.,
Lundh Linnea,
WatkinsChow Dawn E.,
Baxter Laura L.,
PairoCastineira Erola,
Jackson Ian J.,
Oetting William S.,
Pavan William J.,
Adams David R.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24257
Subject(s) - biology , genetics , oculocutaneous albinism , haplotype , locus (genetics) , gene duplication , allele , exon , copy number variation , proband , gene , genome , mutation
Oculocutaneous albinism (OCA) is a heritable disorder of pigment production that manifests as hypopigmentation and altered eye development. Exon sequencing of known OCA genes is unsuccessful in producing a complete molecular diagnosis for a significant number of affected individuals. We sequenced the DNA of individuals with OCA using short‐read custom capture sequencing that targeted coding, intronic, and noncoding regulatory regions of known OCA genes, and genome‐wide association study‐associated pigmentation loci. We identified an OCA2 complex structural variant (CxSV), defined by a 143 kb inverted segment reintroduced in intron 1, upstream of the native location. The corresponding CxSV junctions were observed in 11/390 probands screened. The 143 kb CxSV presents in one family as a copy number variant duplication for the 143 kb region. In the remaining 10/11 families, the 143 kb CxSV acquired an additional 184 kb deletion across the same region, restoring exons 3–19 of OCA2 to a copy‐number neutral state. Allele‐associated haplotype analysis found rare SNVs rs374519281 and rs139696407 are linked with the 143 kb CxSV in both OCA2 alleles. For individuals in which customary molecular evaluation does not reveal a biallelic OCA diagnosis, we recommend preliminary screening for these haplotype‐associated rare variants, followed by junction‐specific validation for the OCA2 143 kb CxSV.