Genetic Epilepsy
Gene: TSPYL1 Green List (high evidence)Green List (high evidence)
Further evidence of seizure phenotypeCreated: 4 Jan 2024, 1:51 a.m. | Last Modified: 4 Jan 2024, 1:51 a.m.
Panel Version: 0.2138
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Sudden infant death with dysgenesis of the testes syndrome MIM#608800
Publications
Green List (high evidence)
First identified in a large Amish family - lethal disease characterized by sudden infant death from cardiorespiratory arrest with dysgenesis of the testes (Puffenberger et al 2004). Cases in non-Amish families reported with additional phenotypic features noted including epilepsy (Slater et al 2020 and Buyse et al 2020)
Sources: Expert list, LiteratureCreated: 7 Oct 2021, 11:50 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Sudden infant death with dysgenesis of the testes syndrome - 608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Publications
Green List (high evidence)
2 new cases of Sudden infant death with dysgenesis of the testes syndrome reported, both with the same frameshift variant:
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.Created: 9 Jan 2021, 11 a.m. | Last Modified: 9 Jan 2021, 11 a.m.
Panel Version: 0.6026
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Publications
I don't know
Limited evidence supporting gene disease association. Single homozygous variant reported in an Amish Community with sudden infant death with dysgenesis of the testes in males. Amber/Red. PMID: 15273283: Homozygous frameshift variant (not present in gnomad) identified in a large Old Order Amish community with sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. PMID: 19463995: 2 heterozygous variants reported in a 46,XY female with complete gonadal dysgenesis and a 46,XY male with idiopathic azoospermia. Both variants present in gnomad 5 hets each and no homozygotes. PMID: 22137496: 2 variants reported with male idiopathic infertility. S140C present in gnomad (8 hets, 0 hom), F366L present (957 hets, 3 homs). Authors concluded that TSPYL1 would not be recommended as part of routine diagnosis screenning. PMID: 25449952; 16418600: Concluded as not causative of the associated phenotype and has limited evidence for screening.Created: 15 Jul 2020, 8:42 a.m. | Last Modified: 15 Jul 2020, 8:42 a.m.
Panel Version: 0.3359
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Sudden infant death with dysgenesis of the testes syndrome (MIM#608800)
Publications
Publications for gene: TSPYL1 were set to 32885560; 15273283; 33075815
Gene: tspyl1 has been classified as Green List (High Evidence).
Gene: tspyl1 has been classified as Green List (High Evidence).
gene: TSPYL1 was added gene: TSPYL1 was added to Genetic Epilepsy. Sources: Expert list,Literature Mode of inheritance for gene: TSPYL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TSPYL1 were set to 32885560; 15273283; 33075815 Phenotypes for gene: TSPYL1 were set to Sudden infant death with dysgenesis of the testes syndrome - 608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124 Review for gene: TSPYL1 was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.