Faculty Collaboration Database

Case Series of Nizon-Isidor Syndrome by Heterozygous Variants in MED12L With Further Evidence of Mitotic Instability in One Case With Diploid-Triploid Mosaicism. Am J Med Genet A 2026 Jan;200(1):205-214

Date

08/21/2025

Pubmed ID

40838347

DOI

10.1002/ajmg.a.64233

Scopus ID

2-s2.0-105013894374 (requires institutional sign-in at Scopus site)

Abstract

Nizon-Isidor syndrome is a rare disorder caused by heterozygous variants in MED12L, with only eight documented cases in the literature. Here, we present three additional cases of this syndrome. Proband 1 was a 7-year-old female who presented with developmental delay, right-leg hemihypertrophy, laryngeal cleft, esotropia, abnormal skin pigmentation, sectoral iris hypopigmentation, dysphagia, periventricular nodular heterotopia, seizures, morbid obesity, and a pelvic kidney. Genome sequencing (GS) revealed a MED12L variant, NM_053002.5:c.3559+2T>G. Both computational models and transcriptomic analysis confirmed that this variant induced splice loss of MED12L exon 25. Probands 2 and 3 presented with overlapping phenotypes of developmental delay; sequencing confirmed c.3441_3444dup; p.(G1149Nfs*13) and seq[GRCh37] del(3)(q25.1q25.1) chr3:g.?_151075120 variants affecting MED12L. Further investigation found diploid-triploid mosaicism in Proband 1, supporting the hypothesis that loss of MED12L function may increase risk for other cytogenetic abnormalities. Probands 2 and 3 did not harbor evidence of additional cytogenetic aberrations. In Proband 1, caloric restriction and semaglutide-pramlintide combination therapy were started at age eight and were effective in weight reduction. Overall, this report expands the phenotypic spectrum of Nizon-Isidor syndrome, highlights a potential link between MED12L and cytogenetic abnormalities, and demonstrates a case of weight loss through GLP-1 therapy in a child with a genetic obesity syndrome.

Author List

Stewart R, Ezell KM, Bell DS, Corner B, McMinn A, Cogan JD, Hamid R, Rives L, Phillips JA 3rd, Paddu N, Srivastava G, Marom R, Ladha FA, Soler-Alfonso C, Franciskovich R, Koziura M, Pruthi S, Richard G, Sheedy CB, Undiagnosed Diseases Network, Cassini T

Authors

James Verbsky PhD, MD Professor in the Pediatrics department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Child
Developmental Disabilities
Female
Heterozygote
Humans
Intellectual Disability
Mediator Complex
Mosaicism
Mutation
Phenotype