A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A

Abstract

A consanguineous Bedouin Israeli kindred presented with a novel autosomal recessive intellectual disability syndrome of congenital microcephaly, low anterior hairline, bitemporal narrowing, low-set protruding ears, strabismus and tented thick eyebrows with sparse hair in their medial segment. Brain imaging demonstrated various degrees of agenesis of corpus callosum and hypoplasia of the vermis and cerebellum. Genome-wide linkage analysis followed by fine mapping defined a 7.67 Mb disease-associated locus (LOD score 4.99 at θ = 0 for marker D10S1653). Sequencing of the 48 genes within the locus identified a single non-synonymous homozygous duplication frameshift mutation of 13 nucleotides (c.2134_2146dup13) within the coding region of FRMD4A, that was common to all affected individuals and not found in 180 non-related Bedouin controls. Three of 50 remotely related healthy controls of the same tribe were heterozygous for the mutation. FRMD4A, member of the FERM superfamily, is involved in cell structure, transport and signaling. It regulates cell polarity by playing an important role in the activation of ARF6, mediating the interaction between Par3 and the ARF6 guanine nucleotide exchange factor. ARF6 is known to modulate cell polarity in neurons, and regulates dendritic branching in hippocampal neurons and neurite outgrowth. The FRMD4 domain that is essential for determining cell polarity through interaction with Par3 is truncated by the c.2134_2146dup13 mutation. FRMD4A polymorphisms were recently suggested to be a risk factor for Alzheimer's disease. We now show a homozygous frameshift mutation of the same gene in a severe neurologic syndrome with unique dysmorphism.

Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability

“…3,4 FRMD4A is a candidate ID gene reported in only a single large pedigree, with a homozygous frame-shift variant. 5 The homozygous missense variant identified in FRMD4A (case 6) does not have any of the previously described features apart from ID, which is mild in our case. One explanation could be that missense variations in FRMD4A will give rise to an alternative phenotype, potentially supported by the ExAC z-score for missense variants (z = 3.23).…”

Arf6 regulates the cycling and the readily releasable pool of synaptic vesicles at hippocampal synapse

“…The use of pharmacological tools to mimic or revert Arf6 function at synapse opens new therapeutic approaches to correct dysregulations of the Arf6 pathway occurring in human neurological diseases associated with mutations in the Arf6 regulatory genes ( Shoubridge et al, 2010 ; Falace et al, 2010 ; Rauch et al, 2012 ; Fine et al, 2015 ).…”

“…While overexpression of the Arf6 GEF msec7-1 has been reported to increase basal synaptic transmission at the Xenopus neuromuscular junction ( Ashery et al, 1999 ), the function of Arf6 at the presynaptic terminal has never been directly addressed. Interestingly, mutations in Arf6 regulatory genes have been recently associated with intellectual disability and epilepsy in humans ( Shoubridge et al, 2010 ; Falace et al, 2010 ; Rauch et al, 2012 ; Fine et al, 2015 ).…”

Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

“…Taking our findings as examples, L1#1 disrupted CNNM2, in which common SNPs are strongly associated with schizophrenia (Fig. 4A) 9 and which is likely a driver gene 10 ; while L1#2 disrupted FRMD4A, associated with a syndrome of microcephaly and intellectual disability 11 , phenotypes observed in carriers of copy number variants that increase risk of schizophrenia 49 . Both genes are expressed in brain and both MEIs reduced gene expression in an experimental assay.…”