SHMT2 – Neurodevelopmental Disorder with Cardiomyopathy, Spasticity, and Brain Abnormalities

This summary reviews the evidence linking biallelic variants in SHMT2 (HGNC:10852) to a neurodevelopmental disorder characterized by cardiomyopathy, spasticity, and brain abnormalities (MONDO:0030866). A series of independent case reports and multi‐patient studies have identified individuals with this disorder, with patients presenting with features such as cardiomyopathy, intellectual disability, peripheral neuropathy, spasticity, as well as additional findings including agenesis of the corpus callosum and delayed speech development. The consistent clinical phenotype across reports supports a genetic etiology and points to a role of SHMT2 in mitochondrial one‑carbon metabolism.

Genetic evidence originates from at least two independent studies. In one report, a novel homozygous missense variant, c.1133A>G (p.Asp378Gly), was identified in a patient by exome sequencing (PMID:35398349). A second study described a 13‑year‑old patient harboring novel compound heterozygous variants, c.1042C>T (p.Arg348Trp) and c.1274G>A (p.Arg425Gln), which further expands the mutational spectrum in SHMT2 (PMID:39589606). In total, prior literature documents seven distinct variants, and the recurrence of missense changes across unrelated probands emphasizes a robust autosomal recessive inheritance pattern.

The genetic findings are supported by segregation data in familial settings, where affected individuals demonstrate biallelic inheritance of pathogenic SHMT2 variants. Although detailed family pedigrees are limited, the consistent observation of autosomal recessive transmission bolsters confidence in the gene-disease association. The reported variants predominantly include missense alterations, and their convergence on a critical metabolic enzyme reinforces the biological plausibility of the pathogenesis in the affected patients (PMID:35398349, PMID:39589606).

Functional assessments suggest that these SHMT2 variants likely disrupt mitochondrial serine hydroxymethyltransferase activity, compromising one-carbon metabolism. Although extensive rescue experiments or patient-specific functional assays have not yet been reported, preliminary biochemical data indicate that the impaired enzymatic function is congruent with the metabolic and neurodevelopmental abnormalities observed in patients. This experimental evidence, while still emerging, supports a pathogenic mechanism based on loss of function.

Integrating the clinical, genetic, and experimental data yields a coherent narrative: multiple independent case reports documenting biallelic SHMT2 variants, supported by segregation and consistent phenotypic features, substantiate a strong gene-disease association. Despite the fact that additional supportive evidence exists beyond the standard ClinGen scoring maximum, the available data are sufficient to guide diagnostic decision-making and inform commercial assay development, as well as future publications.

Key take‑home sentence: Biallelic pathogenic variants in SHMT2 are strongly associated with a neurodevelopmental disorder featuring cardiomyopathy, spasticity, and brain abnormalities, underscoring the enzyme’s critical role in mitochondrial metabolism and neurodevelopment.

References

• European Journal of Medical Genetics • 2022 • Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities PMID:35398349
• Neurogenetics • 2024 • Mild neurodevelopmental disorder due to reduced SHMT2 enzymatic activity caused by novel compound heterozygous variants: expanding the phenotypic spectrum PMID:39589606

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