2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-SINO Syndrome Associated with Heterozygous KIDINS220 Variants: A More Severe Presentation and Maternal Mosaicism

Pdf Summary

Two siblings with a heterozygous nonsense variant in the KIDINS220 gene, associated with SINO syndrome, are described in this study. The siblings have more severe clinical features compared to previously reported cases, including aqueductal stenosis requiring ventriculoperitoneal shunt, G-tube dependence, and significant developmental delays. The healthy mother of the siblings was found to be mosaic for the variant, with approximately 3% of her reads containing the variant.<br /><br />KIDINS220 encodes a membrane protein that plays a significant role in nervous system development. Heterozygous nonsense variants in the last two exons of KIDINS220 have been previously described in patients with SINO syndrome, which is characterized by ventriculomegaly, spastic paraplegia, intellectual disability, nystagmus, and obesity. Most patients with SINO syndrome can ambulate, communicate, and eat by mouth. Truncated proteins that escape nonsense-mediated decay (NMD) have been observed in previous variants, which are mostly located in areas expected to escape NMD.<br /><br />Patients with biallelic pathogenic variants in KIDINS220 generally have loss of function and experience prenatal death with significant ventriculomegaly and contractures. However, the two siblings in this study with a heterozygous variant downstream in exon 29 have more severe clinical features but not as severe as biallelic variants.<br /><br />The mechanism behind the increased severity of symptoms in these patients is unclear. The variant in these patients generate a stop codon farther from the 3' end of the penultimate exon, compared to previous variants. This contradicts the previously proposed mechanism but still overlaps with the previously described phenotype.<br /><br />Further studies are needed to determine the effect of these variants on protein structure and their role in nervous system development. This study highlights the importance of considering maternal mosaicism in the genetic evaluation of patients with SINO syndrome.

Asset Subtitle

Presenting Author - Angela Lee, MD; Co-Author - Jorge Granadillo De Luque, MD, MSc;

Meta Tag

Structure/Function

Pathogenesis

Maternal Genetic Disease

Intellectual disability

Genotype-Phenotype Correlations

Eye disorders

Exome sequencing

Congenital Anomaly

Cognitive Disorders

Clinical History

Brain/Nervous System

Co-Author Jorge Granadillo De Luque, MD, MSc

Presenting Author Angela Lee, MD

Keywords

siblings

heterozygous

nonsense variant

KIDINS220 gene

SINO syndrome

aqueductal stenosis

ventriculoperitoneal shunt

G-tube dependence

developmental delays

maternal mosaicism