Familial p.(Ala73Thr) Variant in GNB2 Associated With Mild Neurodevelopmental Features and Pilocytic Astrocytoma

Pathogenic variants in GNB2 have been associated with a neurodevelopmental disorder that includes global developmental delays and intellectual disability, hypotonia, increased risk for seizures, heart and renal anomalies, and characteristic facial features. Thus far, all reported patients with GNB2-related disorder have had de novo missense variants. Many of these single nucleotide substitutions have been recurrent. Exome sequencing identified a heterozygous GNB2 variant, c.217G>A, predicting p.(Ala73Thr) (NM_005273.3) in a family, including two brothers with developmental delays and their more mildly affected mother. Their mother had a history of very mild developmental delays during childhood, macrocephaly, and subtle facial features consistent with GNB2-related disorder. Consistent with what was observed in this family, this recurrent variant has previously been reported in association with a milder neurocognitive phenotype. However, the findings in this family raise the possibility of an expanded clinical spectrum to include a possible association with overgrowth/macrocephaly and pilocytic astrocytoma. This family also highlights the variable expressivity that can be seen in GNB2-related disorder.