Long Read Sequencing and Expression Studies of AHDC1 Deletions in Xia-Gibbs Syndrome Reveal a Novel Genetic Regulatory Mechanism

Authors

Varuna Chander
Medhat Mahmoud
Jianhong Hu
Zain Dardas
Christopher M Grochowski
Moez Dawood
Michael M Khayat
He Li
Shoudong Li
Shalini Jhangiani
Viktoriya Korchina
Hua Shen
George Weissenberger
Qingchang Meng
Marie-Claude Gingras
Donna M Muzny
Harsha Doddapaneni
Jennifer E Posey
James R Lupski
Aniko Sabo
David R Murdock
Fritz J Sedlazeck
Richard A Gibbs

Language

English

Publication Date

12-1-2022

Journal

Human Mutation

DOI

10.1002/humu.24461

PMID

36054313

PMCID

PMC10167679

PubMedCentral® Posted Date

12-1-2023

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Abnormalities, Multiple, DNA-Binding Proteins, Endoribonucleases, Intellectual Disability, Musculoskeletal Abnormalities, Neurodevelopmental Disorders, Phosphoprotein Phosphatases, Qa-SNARE Proteins, RNA-Binding Proteins, Sphingomyelin Phosphodiesterase, contiguous gene deletion syndromes, gene expression, posttranscriptional gene regulation, rare Mendelian disease traits

Published Open-Access

yes

Recommended Citation

Chander, Varuna; Mahmoud, Medhat; Hu, Jianhong; et al., "Long Read Sequencing and Expression Studies of AHDC1 Deletions in Xia-Gibbs Syndrome Reveal a Novel Genetic Regulatory Mechanism" (2022). Faculty and Staff Publications. 5065.
https://digitalcommons.library.tmc.edu/baylor_docs/5065