STAMBP and microcephaly‑capillary malformation syndrome

STAMBP has been robustly associated with microcephaly‑capillary malformation syndrome, a severe neurocutaneous disorder characterized by congenital microcephaly, intractable epilepsy, profound global developmental delay, and multiple cutaneous capillary malformations. Clinical reports describe patients with additional features such as congenital hypothyroidism, short distal phalanges, spasticity, congenital blindness, and abnormal facial morphology, expanding the recognized phenotypic spectrum (PMID:25266620, PMID:25692795).

Multiple independent case reports and multi‑patient studies have established a strong association between pathogenic variants in STAMBP and the syndrome. Reported cases include families with consanguineous parents leading to homozygous or compound heterozygous mutations, with segregation observed among affected siblings (PMID:27531570, PMID:29907875). In total, over 10 probands from distinct families have been described (PMID:31638258).

Genetic evidence supports an autosomal recessive inheritance model. A diverse variant spectrum comprising missense, loss‑of‑function, and splice mutations has been reported. For instance, the variant c.707C>T (p.Ser236Phe) is one exemplar identified in a patient with severe clinical features; this variant results in destabilization of the encoded protein and impaired STAMBP function, underscoring its pathogenicity (PMID:29907875).

Functional studies have provided critical insights into the molecular mechanisms underlying the syndrome. In vitro assays show that STAMBP deficiency leads to reduced protein expression and aberrant accumulation of ubiquitin‑conjugated protein aggregates, while studies in cellular and organoid models reveal impaired endocytic trafficking and neural progenitor proliferation (PMID:24151880, PMID:36033615). These experimental findings corroborate the genetic data and reinforce the role of STAMBP in normal neural development.

The convergence of robust genetic data from multiple unrelated probands and concordant functional evidence from diverse experimental systems firmly supports a strong gene‑disease association. Moreover, segregation analysis in consanguineous families and the reproducibility of in vitro functional assays enhance the clinical validity of STAMBP testing in patients suspected of microcephaly‑capillary malformation syndrome.

In summary, the integration of genetic and experimental evidence provides compelling support for the pathogenic role of STAMBP variants in microcephaly‑capillary malformation syndrome. This association has significant diagnostic implications, enabling more accurate molecular diagnosis and potentially guiding clinical management. Key take‑home sentence: Molecular testing for STAMBP mutations is essential in the diagnostic evaluation of patients presenting with the complex phenotype of microcephaly and capillary malformations.

References

• Pediatric neurology • 2014 • The microcephaly‑capillary malformation syndrome in two brothers with novel clinical features PMID:25266620
• American journal of medical genetics. Part A • 2015 • Novel STAMBP mutation and additional findings in an Arabic family PMID:25692795
• American journal of medical genetics. Part A • 2016 • Microcephaly‑capillary malformation syndrome: Brothers with a homozygous STAMBP mutation, uncovered by exome sequencing PMID:27531570
• Journal of human genetics • 2018 • A novel homozygous missense mutation in the SH3‑binding motif of STAMBP causing microcephaly‑capillary malformation syndrome PMID:29907875
• Molecular medicine reports • 2019 • Early‑onset epilepsy and microcephaly‑capillary malformation syndrome caused by a novel STAMBP mutation in a Chinese PMID:31638258
• Nature genetics • 2013 • Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly‑capillary malformation syndrome PMID:23542699
• Biochemistry • 2013 • Mechanism of recruitment and activation of the endosome‑associated deubiquitinase AMSH PMID:24151880
• Frontiers in neuroscience • 2022 • Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation PMID:36033615
• Stem cell reviews and reports • 2024 • STAMBP is Required for Long‑Term Maintenance of Neural Progenitor Cells Derived from hESCs PMID:38951308
• Heliyon • 2023 • Novel STAMBP mutations in a Chinese girl with rare symptoms of microcephaly‑capillary malformation syndrome and Mowat‑Wilson syndrome PMID:38058451

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