A novel variant of C12orf4 in a consanguineous Armenian family confirms the etiology of autosomal recessive intellectual disability type 66 with delineation of the phenotype.

BACKGROUND: Intellectual disability (ID) is a feature of many rare diseases caused by thousands of genes. This genetic heterogeneity implies that pathogenic variants in a specific gene are found only in a small number of patients, and difficulties arise in the definition of prevailing genotype and characteristic phenotype associated with that gene. One of such very rare disorders is autosomal recessive ID type 66 (OMIM #618221) caused by defects in C12orf4. Up to now, six families have been reported with mostly truncating variants. The spectrum of the clinical phenotype was not emphasized in previous reports, and detailed phenotype was not always available from previous patients, especially from large cohort studies. METHODS: Exome sequencing was performed in a consanguineous Armenian family with two affected adult brothers. RESULTS: The patients carry a novel homozygous nonsense C12orf4 variant. The integration of previous data and phenotyping of the brothers indicate that the clinical picture of C12orf4 defects involves hypotonia in infancy, rather severe ID, speech impairment, and behavioral problems such as aggressiveness, unstable mood, and autistic features. Several other symptoms are more variable and less consistent. CONCLUSION: This rather nonsyndromic and nonspecific clinical picture implies that additional patients with C12orf4 defects will likely continue to be identified using the "genotype-first" approach, rather than based on clinical assessment. The phenotype needs further delineation in future reports.

Prevention of amyloidosis in familial Mediterranean fever with colchicine: a case-control study in Armenia.

OBJECTIVE: To determine whether or not the use of colchicine decreases the risk of amyloidosis among Armenian patients with familial Mediterranean fever (FMF). SUBJECTS AND METHODS: The study included 99 Armenian patients from the Center of Medical Genetics database with genetically ascertained FMF; 33 had renal amyloidosis and 66 were randomly selected control patients without renal amyloidosis. Self- reported colchicine use was assessed by interviewer-based questionnaire. RESULTS: The patients with incident amyloidosis were more likely to be older men, but younger at the time of disease onset, and more likely to have had a family history of amyloidosis and M694F mutation in the MEFV gene compared to patients without amyloidosis. The risk of amyloidosis decreased with adequate colchicine use rather than nonadequate use (adjusted odds ratio, OR, 0.48, 95% confidence interval, CI, 0.16-1.43), continuous colchicine use rather than interrupted use (adjusted OR 0.15, 95% CI 0.04-0.53), earlier rather than later initiation age of colchicine treatment (adjusted OR 0.95, 95% CI 0.90-1.01), current colchicine rather than ever/never colchicine use (adjusted OR 0.20, 95% CI 0.05-0.89). CONCLUSION: The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2-1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF.