Corpus Callosum, Agenesis Of, With Facial Anomalies And Cerebellar Ataxia

A number sign (#) is used with this entry because of evidence that agenesis of the corpus callosum with facial anomalies and cerebellar ataxia (CCAFCA) is caused by homozygous mutation in the FRMD4A gene (616305) on chromosome 10p13. One such family has been reported.

Clinical Features

Fine et al. (2015) reported a large consanguineous Israeli Bedouin kindred in which 6 individuals had severe congenital microcephaly, severe intellectual disability with very poor or absent speech, and hypertonia at birth which lessened with age. Dysmorphic features included hirsutism with low anterior hairline, arched thick eyebrows, long eyelashes, bitemporal narrowing, low-set posteriorly rotated and protruding ears, strabismus, puffy eyelids, anteverted nares, and protruding lower lip. All had poor overall growth. Patients also had cerebellar signs with ataxia and uncoordinated hand movements; at least 2 were wheelchair-bound. Brain imaging of 4 patients showed full to partial agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia.

Inheritance

The transmission pattern of CCAFCA in the family reported by Fine et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of a large consanguineous Israeli Bedouin kindred with CCAFCA, Fine et al. (2015) identified a homozygous truncating mutation in the FRMD4A gene (616305.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a null allele and complete loss of function. The mutation was predicted to remove an FRMD4A domain essential for determining cell polarity through interaction with PAR3 (601919), thus possibly affecting ARF6 (600464) signaling.