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.