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2023 ACMG Annual Clinical Genetics Meeting Digital ...
SINO Syndrome Associated with Heterozygous KIDINS2 ...
SINO Syndrome Associated with Heterozygous KIDINS220 Variants: A More Severe Presentation and Maternal Mosaicism
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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
Brain/Nervous System
Clinical History
Cognitive Disorders
Congenital Anomaly
Exome sequencing
Eye disorders
Genotype-Phenotype Correlations
Intellectual disability
Maternal Genetic Disease
Pathogenesis
Structure/Function
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
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