TSPYL1 – Sudden Infant Death-Dysgenesis of the Testes Syndrome

TSPYL1 has been implicated in Sudden Infant Death-Dysgenesis of the Testes Syndrome (SIDDT), a rare autosomal recessive disorder characterized by sudden cardiac or respiratory arrest, gonadal dysgenesis in 46,XY individuals, neurologic dysfunction, and uniform fatality before 12 months of age. The gene encodes a nucleosome assembly protein, and biallelic loss-of-function variants in TSPYL1 abrogate its nuclear localization and function.

Initial reports described 21 probands from nine Old Order Amish families with homozygous truncating alleles in TSPYL1 (PMID:32885560). In 2020, a non-Amish infant presenting with feeding difficulties (HP:0011968) and testicular dysgenesis (HP:0000133) was found homozygous for c.725_726delTG (p.Val242GlufsTer52), representing the 22nd case (PMID:32885560). A 2022 study reported a compound heterozygote including the recurrent p.Val242GlufsTer52 allele and reviewed 26 previously described patients, expanding the total to 27 (PMID:36082874).

Segregation analysis across 10 consanguineous pedigrees demonstrated recessive inheritance with absence of heterozygosity spanning ~600 Mb, and fully penetrant co-segregation of biallelic truncating alleles in affected siblings (PMID:32885560; PMID:36082874). The variant spectrum is narrowly defined by frameshift mutations, notably c.725_726delTG (p.Val242GlufsTer52).

Functional assays revealed that the truncated TSPYL1 protein is retained in the Golgi rather than the nucleus in patient fibroblasts, leading to dysregulated cell‐cycle progression, and zebrafish Tspyl1 knockdown recapitulated neurodevelopmental defects and early lethality (PMID:33075815). These data support a loss-of-function mechanism.

A screen of 126 sudden infant death syndrome (SIDS) cases and 261 controls found only heterozygous missense variants and no association with biallelic TSPYL1 mutations, indicating specificity for SIDDT rather than SIDS broadly (PMID:16418600).

Together, the genetic and experimental evidence yields a Strong clinical validity classification. Molecular testing for biallelic TSPYL1 truncating variants is recommended for infants with early lethal cardiorespiratory arrest, gonadal dysgenesis, and neurologic features to confirm SIDDT and guide management.

References

• American journal of medical genetics. Part A • 2020 • Sudden infant death with dysgenesis of the testes syndrome in a non-Amish infant: A case report. PMID:32885560
• American journal of medical genetics. Part A • 2022 • Epileptic encephalopathy as a new feature of the sudden infant death with dysgenesis of the testes syndrome caused by TSPYL1 variants. PMID:36082874
• Human molecular genetics • 2020 • Unravelling the disease mechanism for TSPYL1 deficiency. PMID:33075815
• Genetics in medicine : official journal of the American College of Medical Genetics • 2006 • Genetic investigation of the TSPYL1 gene in sudden infant death syndrome. PMID:16418600

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