Long read sequencing and expression studies of AHDC1 deletions in Xia-Gibbs syndrome reveal a novel genetic regulatory mechanism.

TitleLong read sequencing and expression studies of AHDC1 deletions in Xia-Gibbs syndrome reveal a novel genetic regulatory mechanism.
Publication TypeJournal Article
Year of Publication2022
AuthorsChander, V, Mahmoud, M, Hu, J, Dardas, Z, Grochowski, CM, Dawood, M, Khayat, MM, Li, H, Li, S, Jhangiani, S, Korchina, V, Shen, H, Weissenberger, G, Meng, Q, Gingras, M-C, Muzny, DM, Doddapaneni, H, Posey, JE, Lupski, JR, Sabo, A, Murdock, DR, Sedlazeck, FJ, Gibbs, RA
JournalHum Mutat
Date Published2022 Dec
KeywordsAbnormalities, Multiple, DNA-Binding Proteins, Endoribonucleases, Humans, Intellectual Disability, Musculoskeletal Abnormalities, Neurodevelopmental Disorders, Phosphoprotein Phosphatases, Qa-SNARE Proteins, RNA-Binding Proteins, Sphingomyelin Phosphodiesterase

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.

Alternate JournalHum Mutat
PubMed ID36054313
PubMed Central IDPMC10167679
Grant ListT15 LM007093 / LM / NLM NIH HHS / United States

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