Long‐read genome sequencing resolves a complex 13q structural variant associated with syndromic anophthalmia

Abstract

Microphthalmia, anophthalmia, and coloboma (MAC) are a heterogeneous spectrum of anomalous eye development and degeneration with genetic and environmental etiologies. Structural and copy number variants of chromosome 13 have been implicated in MAC; however, the specific loci involved in disease pathogenesis have not been well‐defined. Herein we report a newborn with syndromic degenerative anophthalmia and a complex de novo rearrangement of chromosome 13q. Long‐read genome sequencing improved the resolution and clinical interpretation of a duplication–triplication/inversion–duplication (DUP‐TRP/INV‐DUP) and terminal deletion. Sequence features at the breakpoint junctions suggested microhomology‐mediated break‐induced replication (MMBIR) of the maternal chromosome as the origin. Comparing this rearrangement to previously reported copy number alterations in 13q, we refine a putative dosage‐sensitive critical region for MAC that might provide new insights into its molecular etiology.

Prenatal diagnosis of distal 13q deletion syndrome in a fetus with esophageal atresia: a case report and review of the literature

“…Previous reports suggested that eye malformation might be associated with the EFNB2 gene [4], and deletion of the 13q32 region [2]. Recently, the 13q33.3-q34 deletion (110,302,002-11,394,979, GPCh37) has been shown to be associated with microphthalmia or anophthalmia with/without coloboma in 15 patients [16], and 13 genes were encoded in the region: IRS2 GPC5 ZIC2 EFNB2 finger anomaly [5,11] Phenotype of the present patient VACTER/VACTEL association [6][7][8]10] hearing loss [23][24][25] Dandy Walker malformation [4,[12][13][14][15] Candidate genes [113862507-113921422] (GpCh37) [7]. In our review of these genes, IRS2 was reported to be involved in retina function [17,18].…”

“…Previous reports suggested that eye malformation might be associated with the EFNB2 gene [ 4 ], and deletion of the 13q32 region [ 2 ]. Recently, the 13q33.3–q34 deletion (110,302,002–11,394,979, GPCh37) has been shown to be associated with microphthalmia or anophthalmia with/without coloboma in 15 patients [ 16 ], and 13 genes were encoded in the region: IRS2 [110405042–110438930], COL4A1 [110801310–110959504], COL4A2 [110959631–111165556], CARS2 [111293757–111358862], ING1 [111364970–111375686], SOX1 [112721463–112726020], ATP11A [113344352–113541482], MCF2L [113623528–113754056], F7 [113760102–113774999], F10 [113777113–113803843], PROZ [113812962–113826700], PCID2 [113831850–113862983] and CUL4A [113862507–113921422] (GpCh37) [ 7 ]. In our review of these genes, IRS2 was reported to be involved in retina function [ 17 , 18 ].…”

Applications of long-read sequencing to Mendelian genetics

“…More than 250 medically relevant genes are more accurately ascertained using LRS-based approaches when compared to SRS [20,21]. In particular, LRS-based approaches can resolve complex SVs [14,[22][23][24], repeat expansions [25,26], and differences in methylation [15] in medically relevant regions or cases that were not solved after standard clinical testing. Finally, LRS, specifically on the ONT platform, is unique in that the data is available for analysis in near real time, which has allowed for studies showing that a complete genome could be sequenced and analyzed in less than 8 h and WGS with targeted analysis for previously known variants could be completed within 3 h [27,28].…”