Microcephaly 10, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-10 (MCPH10) is caused by homozygous or compound heterozygous mutation in the ZNF335 gene (610827) on chromosome 20q13.

Description

Primary microcephaly-10 (MCPH10) is an autosomal recessive disorder characterized by extremely small head size (-9 SD) at birth and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation (summary by Yang et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Clinical Features

Yang et al. (2012) reported a large consanguineous Arab Israeli family in which 8 individuals had severe primary microcephaly (-9 SD) resulting in death by age 1 year in all except 1 case. Brain MRI showed extreme microcephaly with a simplified gyral pattern, absence of the corpus callosum, and delayed myelination. The cerebral cortex was smaller than the skull, suggesting secondary shrinkage and degeneration. Dysmorphic features were reported for some of the patients, and included low sloping forehead, micrognathia, prominent helices, prominent nasal bridge, choanal atresia, and cataracts. Other features included arthrogryposis, joint contractures, and increased tone and spasticity. Neuropathologic examination of 1 patient at age 7 months showed a thinned cortex and neuronal disorganization, with only about 20% of the cortex showing the normal 6 cortical layers. All layers contained fewer neurons compared to normal, and the few neurons that were present showed little apparent polarity or dendritic maturation. The cerebellum was similarly affected, with few Purkinje cells and increased astrocytes, consistent with a degenerative process. Affected individuals also showed lower birth weight and length, indicating reduced somatic size as well.

Sato et al. (2016) reported a 33-month-old girl, born to nonconsanguineous Japanese parents, with severe microcephaly (head circumference more than -5.0 SD), severely impaired intellectual development, and spastic paralysis. Growth (length and weight) were not affected. Prenatal history was unremarkable. At birth, she had a normal head circumference and a small ventricular septal defect. At 3 months of age, she presented with a seizure, at which time her head circumference was -4.6 SD. Facial features included a low sloping forehead and micrognathia. An EEG showed no abnormal findings, and brain MRI showed invisible basal ganglia, hypomyelination, and brainstem hypoplasia. Hearing evaluation showed moderate sensorineural hearing impairment. Ophthalmologic examination showed a subtle corneal scar due to entropium ciliarum.

Stouffs et al. (2018) reported 2 boys with MCPH10. At birth, one boy, of North African descent, had severe microcephaly (head circumference -3.24 SD), low sloping forehead, flat occiput, and generalized hypotonia. He developed seizures with bradycardia and apnea in the first hours of life that were refractory to therapy and led to death at 5 days of age. Brain MRI showed large extraaxial spaces, anterior agyria and a posterior simplified gyral pattern, enlarged ventricles, absent basal ganglia, thin corpus callosum, and hypoplasia of brainstem and cerebellum. Hypomyelination was suspected, but was difficult to assess accurately. At birth, the other boy, of Caucasian European descent, had a normal head circumference (+0.55 SD) but was noted to have body tremors. He developed progressive feeding problems, gastroesophageal reflux disease, frequent spasms, and arching of his back after discharge. At 2 months of age, his head circumference was -0.87 SD. On physical exam, he had a coronal suture ridge, a small anterior fontanel, prominent nasal bridge, truncal and axial hypertonia at rest that was increased with activity, spasticity, frequent tongue thrusting, and hyperreflexia. Brain MRI at age 3 months showed hypomyelination and heterogeneous signal within both thalami with otherwise preserved brain structures. His basal ganglia appeared intact.

Inheritance

The transmission pattern of primary microcephaly in the family reported by Yang et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis of a large consanguineous Arab Israeli family with primary microcephaly, Yang et al. (2012) found linkage to a 2-Mb region on chromosome 20q13.12 (multipoint lod score of 4.54).

Molecular Genetics

In affected members of an Arab Israeli family with MCPH10, Yang et al. (2012) identified a homozygous mutation in the ZNF335 gene (610827.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation caused both a missense change (R1111H) and a splice site defect, resulting in a hypomorphic allele. Patient lymphoblasts showed decreased growth and decreased ZNF335 binding to Ki-67 (176741). Cellular studies indicated that ZNF335 interacts with a chromatin-remodeling complex involving H3K4 methyltransferases, which regulates the expression of specific genes in a variety of pathways; the complex was analogous to the TrxG (trithorax) complex in Drosophila. ZNF335 bound to the promoter of the known neuronal progenitor cell master regulator REST (600571), resulting in its regulation. Patient cell lines showed decreased mRNA levels of REST and decreased H3K4me3 marks at the REST promoter, as well as decreased REST mRNA levels. Finally, in vitro and in vivo mouse models showed that knockdown of Znf335 caused a small brain with absent cortex and disrupted the proliferation and proper differentiation of neuronal cells. The study identified ZNF335 as an essential link between H3K4 complexes and REST, and showed that this pathway regulates human neurogenesis and neuronal differentiation.

In a 33-month-old girl, born to nonconsanguineous Japanese parents, with MCPH10, Sato et al. (2016) identified compound heterozygous missense mutations in the ZNF335 gene (C467R, 610827.0002 and Y504C, 610827.0003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations.

In 2 boys with MCPH10, Stouffs et al. (2018) identified biallelic ZNF335 mutations. One boy, born to consanguineous parents of North African descent, was homozygous for the previously reported C467R mutation. The other boy, born to nonconsanguineous parents of Caucasian European descent, was compound heterozygous for deletion (610827.0004) and missense (610827.0005) mutations.