Sudden death in young peopleGene: TSPYL1
Comment on list classification: Promoting to green as there are now 3 independent cases of patients with plausible disease cause variants in this gene with SIDDT
Created: 9 Jan 2021, 11:07 a.m. | Last Modified: 9 Jan 2021, 11:07 a.m.
Panel Version: 1.15
Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM.
3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported.
PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state.
PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation.
PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL
Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found:
PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control).
PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.
Reports where male infertility cases were screened for TSPYL1 variants:
PMID: 19463995 - Vinci et al 2009 - screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. 2 heterozygous variants reported. One in a 46,XY female with complete gonadal dysgenesis (p.K320R in the conserved NAP domain) and a 46,XY male with idiopathic azoospermia (p.R89H).
PMID: 22137496 - Javaher et al 2012 - screen 104 infertile men for variants in TSPYL1. 2 potentially pathogenic heterozygous variants identified. 1 with azoospermia had a c.419C>G (p.Ser140Cys) variant and 1 with OAT syndrome had the rare c.1098C>A (p.Phe366Leu). However, 1 fertile man was also found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). The authors concluded that TSPYL1 variants did not play a major role in idiopathic male infertility and would not recommend inclusion in diagnostic screening.
Created: 9 Jan 2021, 11:03 a.m. | Last Modified: 9 Jan 2021, 11:03 a.m.
Panel Version: 1.12
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Added 'founder effect' tag on Dec 1st 2016 based on OMIM text: In affected infants with SIDDT (OMIM:608800) from the Belleville Old Order Amish community, Puffenberger et al. (2004, PMID:15273283) identified homozygosity for a 1-bp insertion (457G) in the TSPYL1 gene. All parents were heterozygous for the mutation.
Created: 1 Dec 2016, 1:47 p.m.
Gene: tspyl1 has been classified as Green List (High Evidence).
Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome,608800; SIDDT to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Publications for gene: TSPYL1 were set to
This panel contains genes which aren't arrhythmic or metabolic causes of sudden death with normal post mortem.
TSPYL1 was added to Sudden death in young peoplepanel. Source: Other Model of inheritance for gene TSPYL1 was set to BIALLELIC, autosomal or pseudoautosomal
TSPYL1 was added to Sudden death in young peoplepanel. Sources: Radboud University Medical Center, Nijmegen
TSPYL1 was created by rfoulger