Expanding the clinical spectrum of biallelic ZNF335 variants

Abstract

ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in 2 unrelated families. We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335-associated microcephaly.

Keywords: ZNF335; basal ganglia; microcephaly; neurodegeneration; neurogenesis.

Figure 1

(A–C) Brain MRI at age 4 days of life for patient A. A. Axial T2 shows enlarged subarachnoid spaces, anterior agyria and posterior simplified gyral pattern, enlarged lateral ventricles, absent basal ganglia and white matter hypomyelination. B. Sagital T1 shows hypoplasia of corpus callosum, brainstem and cerebellum. C. Coronal T2 shows severe hypoplasia of the cerebellar vermis and hemispheres. (D–E) Brain MRI at 3 months of life for patient B. D. Axial T1 showing hypomyelination of perirolandic white matter and corona radiata. E. Axial T2 showing age appropriate myelination of posterior limb of the internal capsule as well as heterogeneous signal in thalami and otherwise preserved brain structures. F. Axial T1 showing heterogeneous signal in thalami and otherwise preserved brain structures.