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The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Consanguinity is practiced by around one tenth of the world population but its global distribution is far from uniform. In countries where consanguinity is common, a corresponding increase in the frequency of autosomal recessive diseases is usually observed owing to increased risk of homozygosity for ancestral haplotypes (autozygosity or identity by descent) that harbor pathogenic alleles. The burden of these diseases becomes more apparent as the healthcare system makes gains in its fight against communicable diseases in these countries. Recent advances in molecular genetics make it possible to leverage the mechanism by which consanguinity predisposes to the occurrence of autosomal recessive diseases in order to uncover the causal mutations at an efficient and cost-effective way compared to outbred populations. The identification of these mutations at an unprecedented scale has the potential to significantly reshape the practice of clinical genetics in these populations and to offer opportunities for innovative public health policies. This review discusses the impact that new genomic tools have had on a sample patient population and how they can inform future public health policies in ways that might be relevant to other consanguineous populations., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effect that manifests primarily as renal insufficiency, polydactyly, retinal dystrophy and obesity. The current phenotype-genotype correlation is insufficient to predict the likely causative mutation that makes sequencing of all 14 BBS genes an often necessary but highly complicated way to identify the underlying genetic defect in affected patients. In this study, homozygosity mapping is shown as a robust approach that is highly suited for genetically heterogeneous autosomal recessive disorders in populations in which consanguinity is prevalent. This approach allowed us to quickly identify seven novel mutations in seven families with BBS. Some of these mutations would have been missed by unguided routine sequencing, which suggests that missed mutations in known BBS genes could be more common than previously thought. This study, the largest to date on Saudi BBS families, also revealed interesting phenotypic aspects of BBS, including the first report of non-syndromic retinitis pigmentosa as a novel BBS phenotype.

We describe the third family in the world, after Arabian and Turkish ones, displaying an autosomal recessive autoimmune disease (AID), mimicking systemic lupus erythematosus (SLE), with unusual manifestations due to a homozygous frame-shift variant in DNASE1L3. SLE is a complex AID characterized by multiple organ involvement. Genetic risk variants identified account for only 15% of SLE heritability. Rare Mendelian forms have been reported, including DNASE1L3-related SLE. Through specific genetic tests we identified a homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) in DNASE1L3, predicting frameshift and premature truncation (p.Thr97Ilefs*2). The same mutation was previously reported in three sisters, born from consanguineous parents and affected with hypocomplementemic urticarial vasculitis syndrome (HUVS). As approximately 50% of individuals affected with HUVS develop SLE, it is still unclear whether it is a SLE sub-phenotype or a separate condition. [ABSTRACT FROM AUTHOR]

Microphthalmia is an important inborn error of eye development that can be associated with multisystem involvement. Anophthalmia is more severe and rarer. Single mutations in an expanding list of genes are known to cause this spectrum of anomaly. In one branch of a multiplex family with microphthalmia and anophthalmia, autozygome analysis excluded all known microphthalmia genes at the time of doing this study. Exome sequencing and autozygome filtration identified a novel homozygous variant in ALDH1A3. Subsequently, we identified another homozygous variant in 2 of the 10 probands with microphthalmia we specifically screened for mutations in ALDH1A3. Interestingly, the other branch of the original family was found to segregate anophthalmia/syndactyly with a novel homozygous SMOC1 variant. Our data support the very recent and independent identification of ALDH1A3 as a disease gene in microphthalmia. Locus heterogeneity should be considered in consanguineous families even for extremely rare phenotypes. [ABSTRACT FROM AUTHOR]