Large Saudi Family Research Articles

Cone dystrophy associated with autoimmune polyglandular syndrome type 1

To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.

Whole exome sequencing analysis identifies a missense variant in COL1A2 gene which causes osteogenesis imperfecta Type IV in a family from Saudi Arabia

Objectives: Molecular diagnosis of a large Saudi family presenting an autosomal dominant form of osteogenesis imperfecta (OI). Methods: Genetic analysis of the index patient was performed through 100× paired end whole exome sequencing (WES) covering 24,000 coding genes of the human genome. The causative variant was filtered out among the previously known 23 genes' panel reported for 17 subtypes of OI. The dominant segregation of the causative variant with the disease phenotype was confirmed by Sanger sequencing. Pathogenicity of the altered protein was predicted through SIFT, PolyPhen, and MutationTaster software. Results: A heterozygous variant (c.1801G>A; p. Gly601Ser) in exon 31 of collagen 1α2 was identified. In this study, WES was successfully applied to identify the molecular basis of OI in the proband. The rest of family members were confirmed through Sanger validation confirming the autosomal dominant mode of inheritance in large Saudi family. Conclusion: OI is a rare heterogeneous disorder of connective tissues with 17 overlapping subtypes, for which 23 genes are known. Our work adds to the growing list of disease-causing variants in COL1A2. Reporting the disease-causing variants is one of the best ways to share data for better and accurate variants interpretation. We tested that WES can be used as an efficient tool for the molecular diagnosis of this rare phenotype.

Identification of a novel KCNQ1 mutation in a large Saudi family with long QT syndrome: clinical consequences and preventive implications

Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder that is characterized by prolonged corrected QT (QTc) interval. Mutations in three genes (KCNQ1, KCNH2, and SCN5A) account for the majority of the cases. However, 10 other genes are now known to be implicated in LQTS. In this work, we describe the clinical and molecular analysis in a large Saudi family with LQTS. Screening KCNQ1, KCNH2, and SCN5A genes in the proband, who presented with syncope, led to the identification of a heterozygous mutation (p.H258P) in KCNQ1. An extended clinical and genetic screening of the family identified 11 other members who were carriers for this mutation. All identified carriers had prolonged QTc intervals; yet, only two were symptomatic. Screening the family members for three LQTS modifiers (rs4657139 and rs16847548 in NOS1AP and KCNE1-D85N) did not reveal a correlation with symptoms or QTc intervals. The electrocardiographic and molecular analysis stratified seven carriers at high risk of a cardiac event as they had a QTc of ≥500 ms and were carriers of a KCNQ1 mutation. Our work illustrates the importance of extended family screening in LQTS to identify silent carriers and hence adopt the most appropriate therapeutic and preventive intervention.

Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance

X-linked mental retardation (XLMR) is notably a heterogeneous condition and often poses a diagnostic challenge. The oligophrenin 1 gene (OPHN1) is a protein with a Rho-GTPase-activating domain required in the regulation of the G-protein cycle. Mutations in the OPHN1 cause XLMR with cerebellar hypoplasia and distinctive facial appearance. We report a large Saudi family of four boys and one girl affected with XLMR. The boys had moderate MR, seizure disorder, facial dysmorphism, and cerebellar vermis hypoplasia. The girl had mild MR, seizures, and mild cerebellar hypoplasia. A novel deletion of at least exons 7-15 was identified by polymerase chain reaction analysis and multiple ligation probe amplification of the OPHN1 gene. The array comparative genomic hybridization further delineated approximately 68 kb deletion of the 7-15 exons and nearly half of intron 15. In addition, the X-inactivation confirmed random pattern in the girl. Although the affected boys have remarkably similar phenotype, there was some variability in the severity of the seizure disorder and the cerebellar hypoplasia. The report confirms the previous findings that carrier females may be symptomatic.

Mutation in the SLC4A11 Gene Associated with Autosomal Recessive Congenital Hereditary Endothelial Dystrophy in a Large Saudi Family

Objective: To determine the role of the SLC4A11 gene in two pedigrees affected with autosomal recessive congenital hereditary endothelial dystrophy (CHED). Methods: Nine members of a pedigree from the Kingdom of Saudi Arabia (pedigree 971G) and 2 twins in a pedigree from Bosnia (pedigree GGO413) were diagnosed with autosomal recessive CHED and contributed DNA samples for genetic studies. The proband of each pedigree was tested for disease-causing mutations in the SLC4A11 gene with bi-directional DNA sequencing. Screening assays using restriction enzyme digests were developed to test a cohort of 99 normal control subjects for the presence of SLC4A11 mutations. Results: A novel, homozygous mutation in the SLC4A11 gene (Thr271Met) was detected in the proband of pedigree 971G. Homozygous Thr271Met mutations were detected in all affected members of pedigree 971G. The Thr271Met mutation was not detected in a cohort of 99 normal control subjects. This mutation alters a highly conserved amino acid in the encoded SLC4A11 protein. No SLC4A11 mutations were detected in pedigree GGO413. Conclusion: A novel SLC4A11 mutation (Thr271Met) is associated with autosomal recessive CHED in a pedigree from the Kingdom of Saudi Arabia and provides additional support that mutations in this gene cause disease.

T313M PINK1 Mutation in an Extended Highly Consanguineous Saudi Family With Early-Onset Parkinson Disease

To date, 5 well-confirmed genes for Parkinson disease (PD) have been identified, including 3 autosomal recessive genes: PTEN-induced putative kinase 1 (PINK1), parkin, and DJ-1. Almost nothing is known about the genetics of PD in Saudi Arabia; however, consanguineous families, not infrequent in this population, could be important in the evaluation of known PD genes and the search for new PD factors in the future. To investigate known recessive PD genes in 5 consanguineous Saudi families with PD. The entire open frame as well as the untranslated region and all 5' and 3' intron-exon boundaries of the PINK1, parkin, and DJ-1 genes were sequenced in 5 probands in Saudi families. Four of 5 probands tested negative for PINK1, parkin, and DJ-1 mutations. However, in a large Saudi family with PD with at least 3 consanguineous marriages between first cousins, we detected a threonine to methionine substitution at codon 313 (T313M) PINK1 mutation that affected the kinase domain. Manifestations of the disease in this family included early onset (age, 28-38 years), tremulous movement, slow progression, diurnal fluctuations, bradykinesia, good response to levodopa therapy, and only mild dyskinesias. A neurologist blinded to genetic status clinically evaluated 15 family members, all older than 20 years, and diagnosed PD only in individuals who were later found to be homozygous for the T313M mutation. None of the 13 heterozygotes demonstrated any sign of PD. A homozygous T313M mutation is responsible for PD in this large Saudi family. However, the heterozygous T313M mutation does not act as a PD susceptibility factor, which is in contrast to several reports of mutations affecting only 1 PINK1 allele discovered in sporadic PD.