Microcephaly And Chorioretinopathy, Autosomal Recessive, 1

A number sign (#) is used with this entry because of evidence that autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is caused by homozygous or compound heterozygous mutation in the TUBGCP6 gene (610053) on chromosome 22q13.

Description

Microcephaly and chorioretinopathy is an autosomal recessive developmental disorder characterized by delayed psychomotor development and visual impairment, often accompanied by short stature (summary by Martin et al., 2014).

Genetic Heterogeneity of Microcephaly and Chorioretinopathy

See also MCCRP2 (616171), caused by mutation in the PLK4 gene (605031) on chromosome 4q27, and MCCRP3 (616335), caused by mutation in the TUBGCP4 gene (609610) on chromosome 15q15.

An autosomal dominant form of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is caused by heterozygous mutation in the KIF11 gene (148760) on chromosome 10q23.

See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive pigmentary retinopathy and mental retardation; 268050), which has been mapped to chromosome 8q21.3-q22.1.

Clinical Features

The consistent association of chorioretinopathy in the microcephalic patients reported by McKusick et al. (1966) indicated the existence of an entity distinct from simple microcephaly (251200). The cases of McKusick et al. (1966) were from an inbred conservative Mennonite sect of southern German origin. Schmidt et al. (1968) observed the same association in multiple members of a family. Koch (1968) also found such a case in a population-based study of microcephaly. Cantu et al. (1977) described 2 sisters and a brother with this combination. Kelly (1982) reported a family with 2 affected sibs and suggested the designation 'pseudotoxoplasmosis syndrome.' He noted that the similarity of the chorioretinopathy to that of toxoplasmosis is remarkable.

Parke et al. (1984) described severe microcephaly and retinal pigmentary abnormalities in 2 brothers in a family that had autosomal dominant hyperreflexia as an apparently coincidental trait (see 145290). The different character of the retinal changes may distinguish the disorder in these 2 brothers from that represented by this entry.

Sheriff and Hegab (1988) described a Kuwaiti family in which 3 sibs, 2 boys and a girl, had true microcephaly without mental retardation but with congenital hypertrophy of the retinal pigment epithelium (CHRPE) resembling that of Gardner syndrome (175100). A fourth sib in the family, an 11-year-old boy, had microcephaly (head circumference = 42 cm) but no detectable ophthalmic anomaly. The parents were clinically normal and had no detectable ophthalmic anomalies. A sister of the father, who was married to a cousin, was said to have a son with microcephaly.

Abdel-Salam et al. (2000) stated that 40 cases of microcephaly with chorioretinal dysplasia, some with additional abnormalities, had been reported. They reported 2 unrelated cases, both in Hungarian gypsies, with the additional features of severe mental retardation, epilepsy, and spasticity.

Trzupek et al. (2007) reported a sister and brother with mental retardation, severe microcephaly, hypotonia, and variable retinal and choroidal abnormalities. The 12-year-old girl had multiple atrophic and dysplastic-appearing lesions of the retina and choroid bilaterally; an electroretinogram at 5 months of age revealed markedly subnormal scotopic and photopic responses with delayed flicker timing. Her 5-year-old brother had bilateral macular folds with vitreoretinopathy, serous retinal detachments, glaucoma, and cataracts. Trzupek et al. (2007) stated that these were the first sibs in whom these features were observed with unaffected parents.

Martin et al. (2014) reported 4 patients from 3 unrelated families with primary microcephaly (up to -11 SD), short stature (up to -3.45 SD), delayed psychomotor development, and cone-rod retinal dystrophy. Two patients had a simplified gyral pattern on brain imaging and 1 had nystagmus.

Mapping

Puffenberger et al. (2012) genotyped 4 affected individuals from the original study of McKusick et al. (1966) and 2 patients from another affected pedigree and identified a 1.8-Mb shared block of homozygosity in the subtelomeric region of chromosome 22q22.

Inheritance

Puffenberger et al. (2012) demonstrated that the inheritance pattern of MCCRP1 is autosomal recessive.

Molecular Genetics

In 6 Pennsylvania Mennonite patients with microcephaly and chorioretinopathy mapping to chromosome 22q22, including 4 patients originally studied by McKusick et al. (1966), Puffenberger et al. (2012) identified homozygosity for a read-through variant in the TUBGCP6 gene (X1820G; 610053.0001). The mutation was detected in 4 of 404 Mennonite chromosomes, for a population-specific allele frequency of 0.99%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)

In 4 patients from 3 families with MCCRP1, Martin et al. (2014) identified compound heterozygous mutations in the TUBGCP6 gene (610053.0002-610053.0006). Functional studies of the variants were not performed, but Martin et al. (2014) noted that the TUBGCP6 gene is a direct phosphorylation target of PLK4 (605031), which plays a role in centriole biogenesis. Mutation in the PLK4 gene causes a similar disorder characterized by microcephaly and primordial dwarfism, sometimes with retinal dystrophy (MCCRP2; 616171). Patients with TUBGCP6 or PLK4 mutations did not have a ciliopathy phenotype.