Making sense of genetic heterogeneity

Abstract

Some brain malformations have clinical and imaging features that are so specific they lend themselves readily to the diagnosis of a specific syndrome. The autosomal recessive pontocerebellar hypoplasias (PCH) fall into this category. These disorders feature postnatal progressive microcephaly combined with brainstem and cerebellar hemispheres that are hypoplastic at birth, with the cerebellar vermis relatively spared. To date, 7 PCH clinical syndromes have been described (PCH1–7),1 and subsequent work has demonstrated genetic heterogeneity even within subtypes, with mutations in EXOCS3 , TSEN2 , TSEN34 , TSEN54 , RARS2 , and VRK1 published.2–5