CLINICAL CHARACTERISTICS

-related intellectual disability (ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (≤50%). To date more than 50 individuals with ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some.

DIAGNOSIS/TESTING: The diagnosis of ID is established in a proband with developmental delay or intellectual disability in whom molecular genetic testing identifies either a heterozygous pathogenic variant in (89%) or a deletion of 6p21.3 (11%).

MANAGEMENT

DD/ID are managed as per standard practice. No guidelines are available regarding choice of specific anti-seizure medications (ASMs). In about 50% of affected individuals, the epilepsy responds to a single ASM; in the remainder it is pharmacoresistant. Children may qualify for and benefit from interventions used in treatment of ASD. Consultation with a developmental pediatrician may guide parents through appropriate behavioral management strategies and/or provide prescription medications when necessary. Nasogastric/gastrostomy feeding may be required for individuals with persistent feeding issues. Monitor seizure manifestations and control; behavioral issues; developmental progress and educational needs.

GENETIC COUNSELING

ID is inherited in an autosomal dominant manner. To date almost all probands with ID whose parents have undergone molecular genetic testing have had a germline pathogenic variant; however, vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family. Thus, while the risk to sibs appears to be low, it is presumed to be greater than in the general population because of the possibility of germline mosaicism in a parent. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.