Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Jianhong Hu
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Yunyun Jiang
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
He Li
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Varuna Chander
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Moez Dawood
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
Adam W. Hansen
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Shoudong Li
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Jennifer Friedman
UCSD Departments of Neuroscience and Pediatrics, Rady Children’s Hospital Division of Neurology, Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA
Laura Cross
Department of Pediatrics and Genetics, Children’s Mercy Hospitals, Kansas City, MO, USA
Emilia K. Bijlsma
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Claudia A.L. Ruivenkamp
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Francis H. Sansbury
All Wales Medical Genomics Service, NHS Wales Cardiff and Vale University Health Board, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
Jeffrey W. Innis
Departments of Human Genetics, Pediatrics, and Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Jessica Omark O’Shea
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
Qingchang Meng
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Jill A. Rosenfeld
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Kirsty McWalter
GeneDx, Gaithersburg, MD, USA
Michael F. Wangler
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children’s Neurological Research Institute, Houston, TX, USA
James R. Lupski
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children’s Hospital, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Jennifer E. Posey
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
David Murdock
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Richard A. Gibbs
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Corresponding author
Summary: Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.
