Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder.

Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal-recessive inheritance of CCDD ophthalmic phenotypes. These mutations affected either stability or levels of the protein. We further detected altered levels of sAPP (neuronal protein involved in axon guidance and synaptogenesis) and TUBB3 (encoded by TUBB3, which is mutated in CFEOM3) as a result of null mutations in COL25A1. Our data suggest that lack of COL25A1 might interfere with molecular pathways involved in oculomotor neuron development, leading to CCDD phenotypes.

Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature.

Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.

Analysis of shared homozygosity regions in Saudi siblings with attention deficit hyperactivity disorder.

AIM: Genetic and clinical complexities are common features of most psychiatric illnesses that pose a major obstacle in risk-gene identification. Attention deficit hyperactivity disorder (ADHD) is the most prevalent child-onset psychiatric illness, with high heritability. Over the past decade, numerous genetic studies utilizing various approaches, such as genome-wide association, candidate-gene association, and linkage analysis, have identified a multitude of candidate loci/genes. However, such studies have yielded diverse findings that are rarely reproduced, indicating that other genetic determinants have not been discovered yet. In this study, we carried out sib-pair analysis on seven multiplex families with ADHD from Saudi Arabia. We aimed to identify the candidate chromosomal regions and genes linked to the disease. PATIENTS AND METHODS: A total of 41 individuals from multiplex families were analyzed for shared regions of homozygosity. Genes within these regions were prioritized according to their potential relevance to ADHD. RESULTS: We identified multiple genomic regions spanning different chromosomes to be shared among affected members of each family; these included chromosomes 3, 5, 6, 7, 8, 9, 10, 13, 17, and 18. We also found specific regions on chromosomes 8 and 17 to be shared between affected individuals from more than one family. Among the genes present in the regions reported here were involved in neurotransmission (GRM3, SIGMAR1, CHAT, and SLC18A3) and members of the HLA gene family (HLA-A, HLA-DPA1, and MICC). CONCLUSION: The candidate regions identified in this study highlight the genetic diversity of ADHD. Upon further investigation, these loci may reveal candidate genes that enclose variants associated with ADHD. Although most ADHD studies were conducted in other populations, our study provides insight from an understudied, ethnically interesting population.