Case Series of Nizon-Isidor Syndrome by Heterozygous Variants in MED12L With Further Evidence of Mitotic Instability in One Case With Diploid-Triploid Mosaicism

Authors

• Russell Stewart
• Kimberly M Ezell
• Deanna S Bell
• Brian Corner
• Ashley McMinn
• Joy D Cogan
• Rizwan Hamid
• Lynette Rives
• John A Phillips
• Nina Paddu
• Gitanjali Srivastava
• Ronit Marom
• Farah A Ladha
• Claudia Soler-Alfonso
• Rachel Franciskovich
• Mary Koziura
• Sumit Pruthi
• Gabriele Richard
• Christina B Sheedy
• Undiagnosed Diseases Network
• Thomas Cassini

Language

English

Publication Date

1-1-2026

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.64233

PMID

40838347

PMCID

PMC13282996

PubMedCentral® Posted Date

6-21-2026

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Female, Child, Mosaicism, Mediator Complex, Heterozygote, Phenotype, Intellectual Disability, Developmental Disabilities, Abnormalities, Multiple, Mutation, Nizon-Isidor Syndrome, MED12L, Mediator complex, diploid-triploid mosaicism, mitotic instability, semaglutide

Published Open-Access

yes

Recommended Citation

Stewart, Russell; Ezell, Kimberly M; Bell, Deanna S; et al., "Case Series of Nizon-Isidor Syndrome by Heterozygous Variants in MED12L With Further Evidence of Mitotic Instability in One Case With Diploid-Triploid Mosaicism" (2026). Faculty, Staff and Students Publications. 7148.
https://digitalcommons.library.tmc.edu/baylor_docs/7148