Clinical characteristics: GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues. A subset of individuals show a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. To date, 72 individuals with GRIN1-NDD have been reported.
Diagnosis/testing: The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported).
Management: Treatment of manifestations: Standard treatment of DD/ID, seizures, feeding problems, and behavioral issues.
Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.
Genetic counseling: GRIN1-NDD is inherited in either an autosomal dominant or autosomal recessive manner:
Autosomal dominant inheritance: All probands with a heterozygous GRIN1 pathogenic variant reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant. If the GRIN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the theoretic possibility of parental mosaicism.
Autosomal recessive inheritance: At conception, each sib of an individual with biallelic GRIN1 pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once the GRIN1-NDD pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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