BackgroundPrimary Ciliary Dyskinesia (PCD) is a genetically heterogeneous ciliopathy caused by ultrastructural defects in ciliary or flagellar structure and is characterized by a number of clinical symptoms including recurrent respiratory infections progressing to permanent lung damage and infertility.Case presentationHere we describe our search to delineate the molecular basis in two affected sisters with clinically diagnosed PCD from a consanguineous Saudi Arabian family, in which all known genes have been excluded. A homozygosity mapping-based approach was utilized that ultimately identified one single affected-shared region of homozygosity using 10 additional unaffected family members. A plausible candidate gene was directly sequenced and analyzed for mutations. A novel homozygous missense aberration (p.Lys1154Gln) was identified in both sisters in the DNAH1 gene that segregated completely with the disease phenotype. Further confirmation of this interesting variant was provided by exome-wide analysis in the proband.ConclusionMolecular variation in DNAH1 may play a role in PCD and its potential contribution should be considered in patients where all known genes are excluded.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0162-5) contains supplementary material, which is available to authorized users.

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Maple syrup urine disease (MSUD), an autosomal recessive inborn error of metabolism due to defects in the branched-chain α-ketoacid dehydrogenase (BCKD) complex, is commonly observed among other inherited metabolic disorders in the kingdom of Saudi Arabia. This report presents the results of mutation analysis of three of the four genes encoding the BCKD complex in 52 biochemically diagnosed MSUD patients originating from Saudi Arabia. The 25 mutations (20 novel) detected spanned across the entire coding regions of the BCKHDA, BCKDHB and DBT genes. There were no mutations found in the DLD gene in this cohort of patients. Prediction effects, conservation and modelling of novel mutations demonstrated that all were predicted to be disease-causing. All mutations presented in a homozygous form and we did not detect the presence of a “founder” mutation in any of three genes. In addition, prenatal molecular genetic testing was successfully carried out on chorionic villus samples or amniocenteses in 10 expectant mothers with affected children with MSUD, molecularly characterized by this study.

Glycogen storage disease type IX (GSD IX) is a common form of glycogenosis due to mutations in PHKA1, PHKA2, or PHKB and PHKG2 genes resulting in the deficiency of phosphorylase kinase. The first two genes are X-linked while the latter two follow an autosomal recessive inheritance. The majority of cases of GSD IX are attributed to defects in PHKA2 which usually cause a mild disease. We report three patients with PHKG2-related GSD IX presenting with significant hepatic involvement, fibrosis, and cirrhosis. Interestingly, the homozygosity mapping resolved a dilemma about an erroneously normal phosphorylase kinase activity in patient 1. The novel mutation found in all the three patients (p.G220E) affects the catalytic subunit of the phosphorylase kinase. Increasing evidence shows that patients with PHKG2 mutations have a severe hepatic phenotype within the heterogeneous GSD IX disorder. Therefore, defect in PHKG2 should be considered in patients with suspected glycogenosis associated with significant liver fibrosis and cirrhosis.