Maternal Uniparental Isodisomy of Chromosome 6: A Novel Case of Teratoma and Autism Spectrum Disorder with a Diagnostic and Management Framework

TL;DR

A rare case of maternal uniparental disomy of chromosome 6 is reported, linked to autism and a teratoma, with a proposed diagnostic framework for this ultra-rare condition.

Contribution

A novel case of UPD(6)mat with teratoma and autism is described, along with a diagnostic and management framework for this ultra-rare disorder.

Findings

Complete isodisomy of chromosome 6 and a DIAPH2 variant were identified in the reported case.

IUGR was present in 87% of reviewed UPD(6)mat cases, with most born preterm and small for gestational age.

Neurodevelopmental issues and failure to thrive were common, but no specific gene or epigenetic abnormality was consistently identified.

Abstract

Background: Uniparental disomy (UPD) is the inheritance of both copies of a chromosome from a single parent, leading to distinct genetic conditions. Maternal UPD of chromosome 6 (UPD(6)mat) is extremely rare, with few molecularly confirmed cases reported. Methods: We report a prematurely born female with isodisomic UPD(6)mat, presenting with intrauterine growth restriction (IUGR), developmental delay, autism spectrum disorder, dysmorphic features, and a sacrococcygeal teratoma. In addition, we reviewed 24 confirmed UPD(6)mat cases to assess clinical patterns in prenatal findings, birth outcomes, and postnatal features. Results: Trio whole-exome sequencing revealed complete isodisomy of chromosome 6 and a de novo heterozygous DIAPH2 variant of uncertain significance. In the literature review, IUGR was present in 87% of cases, with most individuals born small for gestational age and preterm. Failure to thrive and neurodevelopmental issues were also frequent. While the exact molecular basis remains unknown, imprinting disturbances—similar to those in UPD(6)pat—and cryptic trisomy 6 mosaicism, particularly in heterodisomy, are the most likely mechanisms. No specific gene or consistent epigenetic abnormality has been identified. Conclusions: This study aims to enhance the understanding of the genetic and phenotypic spectrum of UPD(6)mat, improving diagnostic and management approaches for this ultra-rare genetic disorder. We propose a detailed list of clinical assessments and tests to be performed following the detection of maternal uniparental disomy of chromosome 6.

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