Two novel cases of biallelic SMPD4 variants with brain structural abnormalities
Shintaro Aoki1,2, Kazuki Watanabe1, Mitsuhiro Kato3
1Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
Neurogenetics
|October 26, 2023
Summary
Novel loss-of-function variants in Sphingomyelin phosphodiesterase 4 (SMPD4) cause syndromic neurodevelopmental disorders. This study identified three new variants linked to microcephaly, intellectual disability, and diverse brain abnormalities.
Area of Science:
- Genetics and Molecular Biology: Focuses on the genetic underpinnings of neurodevelopmental disorders.
Background:
- Sphingomyelin phosphodiesterase 4 (SMPD4) deficiency is linked to syndromic neurodevelopmental disorders.
- Characterized by microcephaly, congenital arthrogryposis, and brain anomalies.
Approach:
- Exome sequencing identified three novel SMPD4 loss-of-function variants in two patients.
- RNA analysis and minigene assays investigated variant effects on mRNA stability and function.
Key Points:
- Patient 1: Homozygous SMPD4 variant (c.740_741del) causing profound intellectual disability and specific brain abnormalities.
- Patient 2: Compound heterozygous variants (c.2124_2125del and c.1188+2dup) leading to a wide spectrum of developmental and neurological issues.
- The c.1188+2dup variant causes exon skipping and potential nonsense-mediated mRNA decay.
Conclusions:
- Identified novel SMPD4 variants expand the known mutation spectrum for SMPD4-related neurodevelopmental disorders.
- Highlights the phenotypic diversity associated with SMPD4 deficiency, ranging from intellectual disability to complex syndromic presentations.
- Further research is needed to fully elucidate the genotype-phenotype correlations and pathogenic mechanisms.
