ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation

摘要

Objective: We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. Methods: Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. Results: A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. Conclusions: ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy. X-chromosomal mutations are a common cause of intellectual disability (X-linked intellectual disability [XLID]) in males accounting for 10%–12% of ID. 1 , 2 XLID is highly heterogeneous and is usually divided into syndromic and nonsyndromic forms, depending on the association with particular clinical findings. 1 , 2 Epileptic seizures accompany XLID in almost half the disorders, in some beginning in infancy prior to the developmental delay being evident. Recent next-generation sequencing (NGS) approaches have expedited the identification of XLID genes, including those associated with epilepsy, 1 , – 3 many of which encode proteins involved in synaptic function. 4 ARHGEF9 is one such gene, 5 , – 9 encoding collybistin (Cb), a brain-specific guanine nucleotide exchange factor with an essential role in inhibitory synaptic transmission. 5 Cb interacts with the inhibitory receptor–anchoring protein gephyrin and is required for the formation of gephyrin and gephyrin-dependent GABA_A clusters in the postsynaptic membrane ( figure 1 ). 5 , 8 , 10 Cb knockout mice exhibit increased anxiety, impaired spatial learning, and convulsions. 10 , 11 Figure 1 Interaction of collybistin in the postsynaptic membrane Over 10 patients with ARHGEF9 mutations have been reported, 5 , – 9 , 12 , – 15 indicating that this will likely be one of the more common XLIDs. Descriptions of the published cases vary from scant (in large NGS projects) to case reports with substantial detail. In the present study, we combine detailed descriptions of the phenotypes of 18 patients with ARFGH9 mutations. In 4 cases, adequate detail was present at first published description. In 6 cases, we went back to the patients mentioned in tables of NGS results and worked with their physicians to obtain clinical details. The remaining are new unpublished patients.