A number sign (#) is used with this entry because of evidence that sudden infant death with dysgenesis of the testes syndrome (SIDDT) is caused by mutation in the testis-specific protein-like-1 gene (TSPYL1; 604714) on chromosome 6q22.

Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is characterized by sudden cardiac or respiratory arrest, disordered testicular development, and neurologic dysfunction, and is uniformly fatal before 1 year of age (Slater et al., 2020).

Puffenberger et al. (2004) identified a syndrome of sudden infant death with dysgenesis of the testes in 21 individuals from 9 sibships among the Belleville Old Order Amish community. The condition was not seen among the Lancaster County Old Order Amish population. Affected infants appeared normal at birth, but developed signs of visceroautonomic dysfunction early in life followed by death before age 12 months of abrupt cardiorespiratory distress. Features included bradycardia, hypothermia, severe gastroesophageal reflux, laryngospasm, bronchospasm, and abnormal cardiorespiratory patterns during sleep. Postmortem examination of 2 infants showed no neuropathologic abnormalities; specifically, the brainstem and anterior horn cells were normal. Genotypic males with SIDDT had fetal testicular dysgenesis and ambiguous genitalia, with findings such as intraabdominal testes, dysplastic testes, deficient fetal testosterone production, fusion and rugation of the gonadal sac, and partial development of the penile shaft. Female sexual development was normal. Affected infants had an unusual staccato cry described as similar to the cry of a goat.

Slater et al. (2020) reported a non-Amish 46,XY phenotypically female infant with SIDDT and mutation in the TSPYL1 gene. At birth she exhibited hypothermia, apnea on attempted feeding, and abnormal nonsustained jerking movements. Electroencephalogram (EEG) did not show evidence of seizures, and head ultrasound was normal. She had mild facial dysmorphisms, including a right ear that was smaller than the left ear with hypoplastic helices, upslanting palpebral fissures, hooded eyelids, and anteverted nares. Echocardiogram showed a small muscular ventricular septal defect and patent foramen ovale. Stridor was noted and endoscopy revealed laryngomalacia. Patellar reflexes were difficult to elicit, and her lower extremities were held in tight flexion. External genitalia appeared normal for a premature female infant, but pelvic ultrasound revealed no uterus or adnexal structures, with no gonads visible. Evaluation for low T-cell receptor excision circles (TRECs) observed on newborn screening showed mild T-cell lymphopenia of unclear etiology. The patient began having EEG-confirmed seizures and was diagnosed with intractable epilepsy, with multiple episodes of status epilepticus. She eventually developed respiratory failure and died at 8 months of age after withdrawal of life-sustaining therapy.

The transmission pattern of SIDDT in the families reported by Puffenberger et al. (2004) was consistent with autosomal recessive inheritance.

Using a high-density SNP genome scan, Puffenberger et al. (2004) localized the SIDDT disease locus to a 3.6-Mb interval on chromosome 6q22.1-q22.31 (maximum 2-point lod score of 2.41).

In 21 affected patients with SIDDT, Puffenberger et al. (2004) identified a homozygous mutation in the TSPYL1 gene (604714.0001). All parents of affected infants were heterozygous for the mutation, and no unaffected sibs were homozygous for the mutation.

In a non-Amish 46,XY phenotypically female infant with SIDDT, Slater et al. (2020) performed chromosomal microarray hybridization analysis and detected a large amount of absence of heterozygosity across multiple chromosomes, suggesting a close familial relationship between the proband's biological parents. Whole-exome sequencing (WES) identified a homozygous 2-bp deletion in the TSPYl1 gene (604714.0002) for which the proband's mother was heterozygous; no paternal DNA sample was available for analysis. The authors noted that in addition to characteristics closely resembling those of the Amish patients with SIDDT reported by Puffenberger et al. (2004), this patient also had intractable epilepsy and mild T-cell lymphopenia. No known epilepsy- or immunodeficiency-associated variants were detected on WES.