-Related Neurodevelopmental Disorder

CLINICAL CHARACTERISTICS

-related neurodevelopmental disorder (-NDD) is characterized by two phenotypes: -NDD due to gain-of-function variants and -NDD due to loss-of-function variants. -NDD due to gain-of-function variants within the spectrin repeat domain is characterized by moderate-to-severe developmental delay, intellectual disability, macrocephaly (or relative macrocephaly), neurobehavioral manifestations (poor attention, stereotypies, obsessive-compulsive behavior, aggressive behavior, and autism spectrum disorder), and early feeding difficulties with poor weight gain and growth deficiency. Seizures, constipation, scoliosis, dental abnormalities, and cardiac anomalies are also reported. -NDD due to loss-of-function variants is characterized by mild-to-moderate developmental delay and intellectual disability, microcephaly, neurobehavioral manifestations (poor attention, aggressive behavior, autism spectrum disorder, obsessive-compulsive traits, and stereotypies), early feeding difficulties with poor weight gain, dental abnormalities, and digit anomalies, including 2-3 toe syndactyly in some individuals. Seizures, constipation, scoliosis, and cardiac anomalies are also reported.

DIAGNOSIS/TESTING: The diagnosis of NDD is established in a proband with a heterozygous pathogenic variant identified by molecular genetic testing.

MANAGEMENT

Treatment is symptomatic and includes routine management of developmental delays, intellectual disability, neurobehavioral manifestations, seizures, feeding difficulties, gastroesophageal reflux, constipation, spine abnormalities, and dental abnormalities, as well as for rarely occurring cardiovascular anomalies and recurrent infections. At each visit, monitor developmental progress and educational needs; behavioral assessments for attention, aggression, and/or social communication difficulties; growth and feeding assessments to ensure optimal nutritional status; assessment for seizures, constipation, spine deformities, and frequent infections; regular dental evaluations.

GENETIC COUNSELING

-NDD is an autosomal dominant disorder. The majority of individuals diagnosed with -NDD have the disorder as a result of a pathogenic variant; approximately 15% inherited the pathogenic variant from an affected parent. gain-of-function missense variants (affecting the spectrin repeat domain) and loss-of-function missense variants (within the GEFD1 domain) are typically . loss-of-function truncating variants may occur or be inherited from an affected parent. Each child of an individual with -NDD has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.