Long read sequencing and expression studies of AHDC1 deletions in Xia‐Gibbs syndrome reveal a novel genetic regulatory mechanism. Issue 12 (24th September 2022)

• Record Type: Journal Article
• Authors: Chander, Varuna; Mahmoud, Medhat; Hu, Jianhong; Dardas, Zain; Grochowski, Christopher M.; Dawood, Moez; Khayat, Michael M.; Li, He; Li, Shoudong; Jhangiani, Shalini; Korchina, Viktoriya; Shen, Hua; Weissenberger, George; Meng, Qingchang; Gingras, Marie‐Claude; Muzny, Donna M.; Doddapaneni, Harsha; Posey, Jennifer E.; Lupski, James R.; Sabo, Aniko; Murdock, David R.; Sedlazeck, Fritz J.; Gibbs, Richard A.
• Is Part Of: Human mutation. Volume 43:Issue 12(2022)
• Page Start: 2033
• Page End: 2053
• Publication Date: 2022-09-24
• Subjects: contiguous gene deletion syndromes -- gene expression -- posttranscriptional gene regulation -- rare Mendelian disease traits; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24461
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Xia‐Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein‐truncating mutations in the AT‐Hook DNA binding motif containing 1 ( AHDC1 ) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight other genes within chr1p36.11 ( Feline Gardner‐Rasheed, IFI6, FAM76A, STX12, PPP1R8, THEMIS2, RPA2, SMPDL3B ) and terminating within the first intron of AHDC1 . The breakpoint junctions and phase of the deletion were identified using both short and long read sequencing (Oxford Nanopore). Quantification of RNA expression patterns in whole blood revealed that AHDC1 exhibited a mono‐allelic expression pattern with no deficiency in overall AHDC1 expression levels, in contrast to the other deleted genes, which exhibited a 50% reduction in mRNA expression. These results suggest that AHDC1 expression in this individual is compensated by a novel regulatory mechanism and advances understanding of mutational and regulatory mechanisms in neurodevelopmental disorders.