Association Between Invisible Basal Ganglia and ZNF335 Mutations: A Case Report

Abstract

ZNF335 was first reported in 2012 as a causative gene for microcephaly. Because only 1 consanguineous pedigree has ever been reported, the key clinical features associated with ZNF335 mutations remain unknown. In this article, we describe another family harboring ZNF335 mutations. The female proband was the first child of nonconsanguineous Japanese parents. At birth, microcephaly was absent; her head circumference was 32.0 cm (−0.6 SD). At 3 months, microcephaly was noted, (head circumference, 34.0 cm [−4.6 SD]). Brain MRI showed invisible basal ganglia, cerebral atrophy, brainstem hypoplasia, and cerebellar atrophy. At 33 months, (head circumference, 41.0 cm [−5.1 SD]), she had severe psychomotor retardation. After obtaining informed consent from her parents, we performed exome sequencing in the proband and identified 1 novel and 1 known mutation in ZNF335, namely, c.1399T>C (p.C467R) and c.1505A>G (p.Y502C), respectively. The mutations were individually transmitted by her parents, indicating that the proband was compound heterozygous for the mutations. Her brain imaging findings, including invisible basal ganglia, were similar to those observed in the previous case with ZNF335 mutations. We speculate that invisible basal ganglia may be the key feature of ZNF335 mutations. For infants presenting with both microcephaly and invisible basal ganglia, ZNF335 mutations should be considered as a differential diagnosis.

Expanding the clinical spectrum of biallelic ZNF335 variants

“…In contrast, homozygosity of the ZNF335 p.(Cys467Arg) variant results in severe congenital microcephaly, generalized hypotonia, and refractory seizures leading to death at 5 days of age with multiple structural brain anomalies. The c.1399 T > C, p.(Cys467Arg) variant described in patient A was also previously reported in a compound heterozygous state with c.1505A > G, p.(Tyr502Cys) in a child with a milder clinical phenotype characterized by a less severely affected cerebral cortex as seen on MRI and survival beyond 33 months . It might be hypothesized that the homozygous p.(Cys467Arg) missense mutation detected in patient A is affecting the structure of the ZNF335 protein and consequently results in a more severe phenotype.…”

“…Including this report, of the 10 patients with biallelic ZNF335 variants reported to date (7 males, 3 females), only 2 girls survived beyond the age of 18 months. In all cases, death was likely secondary to respiratory complications or seizures (Current report, Yang et al 2012, Sato et al 2016).…”

“…However, the differential diagnosis of microcephaly and hypomyelination is quite broad, necessitating a comprehensive environmental, metabolic and genetic evaluation. The presence of epilepsy was variable in the 4 families, with patient A demonstrating refractory seizures leading to death at age 5 days, whereas the proband in Sato et al had rare focal seizures controlled by treatment and patient B lacked any clinical seizures, but has frequent spasms that have yet to be recorded by EEG. Although not noted by Yang et al, affected individuals in that family had seizures described as paroxysmal myoclonic jerks (personal communication).…”

“…Mouse models with Znf335 null mutations are embryonically lethal while a conditional knockout of Znf335 leads to severely reduced cortical size . Biallelic variants in ZNF335 have been reported as the cause of autosomal recessive congenital or acquired microcephaly in 2 independent families, with severe spastic quadriplegia and increased extra‐axial spaces, absence of the basal ganglia, absent or hypoplastic corpus callosum, enlarged ventricles, markedly reduced white matter volume, delayed myelination, hypoplasia of the brainstem, cerebellar hemispheres and vermis on brain imaging. Variants in ZNF335 in the previously reported families included a homozygous c.3332G > A, p.(Arg1111His) variant that affects the 5′ splice site of exon 20, as well as compound heterozygous missense variants c.1399 T > C, p.(Cys467Arg) and c.1505A > G, p.(Tyr502Cys) .…”

“…Biallelic variants in ZNF335 have been reported as the cause of autosomal recessive congenital or acquired microcephaly in 2 independent families, with severe spastic quadriplegia and increased extra‐axial spaces, absence of the basal ganglia, absent or hypoplastic corpus callosum, enlarged ventricles, markedly reduced white matter volume, delayed myelination, hypoplasia of the brainstem, cerebellar hemispheres and vermis on brain imaging. Variants in ZNF335 in the previously reported families included a homozygous c.3332G > A, p.(Arg1111His) variant that affects the 5′ splice site of exon 20, as well as compound heterozygous missense variants c.1399 T > C, p.(Cys467Arg) and c.1505A > G, p.(Tyr502Cys) . Here we report 1 individual with 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 in ZNF335 and further delineate the associated clinical spectrum of ZNF335 ‐related severe primary autosomal recessive microcephaly.…”