Prevalence
So far, only five patients with an heterozygous mutation in SPOP leading to a LoF have been reported in the medical literature. Nevertheless, more individuals will likely be found as genetic testing is more commonly used for undiagnosed intellectual disability.
Main clinical features
Heterozygous pathogenic LoF variants in the SPOP gene that result in a dominant-negative effect cause Nabais Sa-de Vries syndrome type 2, which is characterized by:
• global developmental delay apparent from infancy;
• behavioral and sleeping problems.
• facial dysmorphism
• (relative) macrocephaly and growth disturbance
• cardiovascular abnormalities
• endocrine abnormalities
• epilepsy
Diagnosis
SPOP variants can be identified using molecular genetic testing, either by:
•sequencing of the SPOP gene;
•exome/genome sequencing.
To ascertain whether the variant cause a GoF (NSDVS1) or a LoF/dominant-negative effect (NSDVS2) the BET protein amounts should be measured for each variant introduced in an isogenic model system (human Ishikawa endometrial cancer cells).
Inheritance
NSDVS2 is inherited in an autosomal dominant manner.
To date, all known patients represented sporadic cases (i.e. a single occurrence in a family), resulting from a de novo pathogenic variant in SPOP. Thus, the recurrence risk for future pregnancies is considered low (probably <1%) based upon the current knowledge.
SPOP LoF