Expanding the <i>SIAH1</i>‐Associated Phenotypic Spectrum: Insights From Loss‐of‐Function Variants

SIAH1 encodes for a RING-type E3 ubiquitin ligase involved in protein ubiquitination. More specifically, it positively regulates Wnt signaling through promoting the accumulation of β-catenin and mediates ubiquitination and degradation of Akt3 in neural development. Heterozygous de novo missense pathogenic variants in SIAH1 have been described in five unrelated individuals and are associated with developmental delay, hypotonia, and dysmorphic features. In this report, we present additional individuals from eight unrelated families and their clinical and genetic findings. We identified two missense and six predicted loss-of-function variants. Motor and speech delay and intellectual disabilities of varying severity were observed in all individuals. Neurodevelopmental issues, as well as infantile hypotonia and facial dysmorphism, were observed in the majority of individuals. Hearing loss, gastroesophageal reflux disease or other gastrointestinal issues, endocrinology abnormalities, and recurrent infections were observed in over 50% of individuals. This study expands the phenotypic spectrum of this syndrome and emphasizes the diverse impact of SIAH1 variation on multi-system clinical manifestations.

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Publication Details

Journal
American Journal of Medical Genetics Part A
Published
2025-03-29
DOI
https://doi.org/10.1002/ajmg.a.64048
Citations
2
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
3.63
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article

Expanding the SIAH1‐Associated Phenotypic Spectrum: Insights From Loss‐of‐Function Variants

Mira Irons, Trevor L. Hoffman, Brandon K. Walther, Diana Le Duc et al.
2 citations
American Journal of Medical Genetics Part A
Genomics and Rare Diseases
3.63
article

Expanding the SIAH1‐Associated Phenotypic Spectrum: Insights From Loss‐of‐Function Variants

Mira Irons, Trevor L. Hoffman, Brandon K. Walther, Diana Le Duc, Lucy Hanington, Liza Douiev, Oliver Murch, Deborah Shears, Amaia Lasa‐Aranzasti, Helen Livesey, Tamar Harel, M. R. Frank, Akash Kumar, Jenny Kim, Paula Fernández‐Álvarez
article en
2 citations

Abstract

SIAH1 encodes for a RING-type E3 ubiquitin ligase involved in protein ubiquitination. More specifically, it positively regulates Wnt signaling through promoting the accumulation of β-catenin and mediates ubiquitination and degradation of Akt3 in neural development. Heterozygous de novo missense pathogenic variants in SIAH1 have been described in five unrelated individuals and are associated with developmental delay, hypotonia, and dysmorphic features. In this report, we present additional individuals from eight unrelated families and their clinical and genetic findings. We identified two missense and six predicted loss-of-function variants. Motor and speech delay and intellectual disabilities of varying severity were observed in all individuals. Neurodevelopmental issues, as well as infantile hypotonia and facial dysmorphism, were observed in the majority of individuals. Hearing loss, gastroesophageal reflux disease or other gastrointestinal issues, endocrinology abnormalities, and recurrent infections were observed in over 50% of individuals. This study expands the phenotypic spectrum of this syndrome and emphasizes the diverse impact of SIAH1 variation on multi-system clinical manifestations.

American Journal of Medical Genetics Part AVol. 197(8)
Boston Children's Hospital (US), Harvard University (US), Hebrew University of Jerusalem (IL), Hadassah Medical Center (IL), Vall d'Hebron Institut de Recerca (ES), Vall d'Hebron Hospital Universitari (ES), Stanford Medicine (US), Kaiser Permanente Anaheim Medical Center (US), Oxford University Hospitals NHS Trust (GB), Klinikum Chemnitz (DE), Cardiff University (GB)
Openalex Percentile: Top 9%
Genomics and Rare Diseases
3.63
DOIOpen Access PDFOpenAlex
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