Microcephaly 16, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that primary autosomal recessive microcephaly-16 (MCPH16) is caused by homozygous or compound heterozygous mutation in the ANKLE2 gene (616062) on chromosome 12q24.

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

Clinical Features

Yamamoto et al. (2014) reported a boy, born of unrelated parents of Mexican descent, with severe primary microcephaly. At birth he showed a very small head with low sloping forehead, ptosis, small jaw, and spastic quadriplegia. He also had multiple hyper- and hypopigmented macules all over his body as well as undescended testes. During the first year of life, he had unexplained anemia and glaucoma. At age 3 years, he developed seizures manifest as staring episodes with facial twitching. At age 5.5 years, he had severe microcephaly (-9 SD), short stature (-6 SD), severe spastic quadriplegia, adducted thumbs, and knee contractures. He had good eye contact, but open mouth with drooling. Brain imaging as a newborn showed markedly simplified gyral pattern, mildly thickened cortex, small frontal horns and mildly enlarged posterior horns of the lateral ventricles, and agenesis of the corpus callosum. The brainstem and cerebellum appeared relatively normal. A younger sister had severe microcephaly, spasticity, and abnormal skin pigmentation, but died in the first few weeks of life from cardiac failure.

Shaheen et al. (2019) described 3 patients with microcephaly and mutation in the ANKLE2 gene. The first patient was a Sudanese girl (13DG0559), born to consanguineous parents, with microcephaly since birth. Brain imaging showed agenesis of the posterior part of the corpus callosum. She had normal developmental milestones, and her physical examination was unremarkable. The second patient (MC22901) was a 15-year-old girl, born to consanguineous Indian parents, who presented with microcephaly, impaired intellectual development, hyperactivity, and irregular sleep-wake rhythm. At birth her head circumference (OFC) was -6 SD and weight -2.3SD. Her current motor development seemed appropriate for age, and her current OFC was -16.3 and weight -2.8 SD. Head CT scan was within normal limits. The third patient was a 14-year-old boy whose OFC at birth was -4.33 SD and weight -2.05 SD. Dysmorphic features included sloping forehead, overriding sutures, micrognathia, mild convergent strabismus, high and broad nasal bridge, and a high-arched palate. Head ultrasound after birth showed bilateral subependymal hemorrhage. At age 13 years, his OFC was less than the first percentile. He had severe global developmental delay affecting all domains, autism spectrum disorder, and attention deficit-hyperactivity symptoms. Brain imaging showed severely diminished cerebral hemispheric volume, microlissencephaly of the cerebellum, hypoplasia of the cerebellar vermis, partial agenesis of the corpus callosum, particularly the posterior body and rostrum, colpocephaly, coarsening of the gyral sulcal pattern, and some thickening consistent with pachygyria.

Inheritance

The transmission pattern of MCPH16 in the family reported by Yamamoto et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of unrelated Mexican parents, with MCPH16, Yamamoto et al. (2014) identified compound heterozygous mutations in the ANKLE2 gene (616062.0001 and 616062.0002). One of the mutations was a nonsense mutation and the other was a missense mutation. Functional studies of the variants were not performed, but a Drosophila mutant showed a small brain with decreased cell proliferation and increased apoptosis of neuroblasts. The mutations were found by a combination of whole-exome sequencing and analysis of genes potentially involved in neurologic diseases that were identified in a gene ontology comparison with essential Drosophila genes. Each unaffected parent was heterozygous for 1 of the mutations.

By targeted exome or whole-exome sequencing in a cohort of 137 families in which a child had primary microcephaly, Shaheen et al. (2019) identified a Sudanese girl, born of consanguineous parents, who was homozygous for a missense mutation in the ANKLE2 gene. Through an international collaboration, they identified 2 additional unrelated children who were both homozygous for a mutation in the ANKLE2 gene (G201W; 616062.0002).

Animal Model

Yamamoto et al. (2014) identified a mutation in the Drosophila homolog of the ANKLE2 gene. The mutation caused a loss of thoracic bristles and underdevelopment of the sensory organs, as well as increased lethality. In the third larval stage, the brain became progressively smaller than wildtype, and this and the lethal phenotype could be rescued by expression of wildtype human ANKLE2. Analysis of brain from Drosophila Ankle2 mutants showed decreased number of neuroblasts, decreased mitosis and cell proliferation, and increased apoptosis.