MGA-related syndrome: A proposed novel disorder

Bobbi McGivern; Michelle M Morrow; Erin Torti; Kirsty McWalter; Ingrid M Wentzensen; Kristin G Monaghan; Amanda Gerard; Laurie Robak; David Chitayat; Claire Botsford; Sarah Jurgensmeyer; Peter Leahy; Paul Kruszka

doi:10.1016/j.xhgg.2024.100387

MGA-related syndrome: A proposed novel disorder

HGG Adv. 2024 Nov 26;6(1):100387. doi: 10.1016/j.xhgg.2024.100387. Online ahead of print.

Affiliations

¹ GeneDx, LLC, Gaithersburg, MD, USA. Electronic address: [email protected].
² GeneDx, LLC, Gaithersburg, MD, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
⁴ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for SickKids, University of Toronto, Toronto, ON, Canada.
⁵ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
⁶ Division of Genetics, Genomics, and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

PMID: 39600096
DOI: 10.1016/j.xhgg.2024.100387

Abstract

MGA (OMIM: 616061) encodes a dual-specificity transcription factor that regulates the expression of Max-network and T-box family target genes, important in embryogenesis. Previous studies have linked MGA to various phenotypes, including neurodevelopmental disorders, congenital heart disease, and early-onset Parkinson's disease. Here, we describe the clinical phenotype of individuals with de novo, heterozygous predicted loss-of-function variants in MGA, suggesting a unique disorder involving both neurodevelopmental and congenital anomalies. In addition to developmental delays, certain congenital anomalies were present in all individuals in this cohort including cardiac anomalies, male genital malformations, and craniofacial dysmorphisms. Additional findings seen in multiple individuals in this cohort include hypotonia, abnormal brain imaging, hearing loss, sleep dysfunction, urinary issues, skeletal abnormalities, and feeding difficulties. These findings provide support for MGA as a gene intolerant to protein truncation with a broad phenotypic spectrum.

Keywords: MGA; candidate gene; clinical exome sequencing; congenital anomalies; congenital heart defect; craniofacial dysmorphism; gene discovery; genetic testing; hearing loss; neurodevelopmental disorder.