Variable phenotype of a null PPP1R13L allele in children with dilated cardiomyopathy.

Childhood-onset cardiomyopathy is a genetically heterogeneous group of conditions with several genes implicated. Recently, biallelic loss-of-function variants in PPP1R13L have been reported in association with a syndromic form of dilated cardiomyopathy (DCM). In addition, affected children manifest skin and hair abnormalities, cleft lip and palate (CLP), and eye findings. Here, we delineate the condition further by describing the phenotype associated with a homozygous frameshift variant (p.Arg330 ProfsTer76) in PPP1R13L detected in two sibships in a consanguineous family with six affected children. The index case had DCM and wooly hair, two of his siblings had DCM and CLP while three cousins had, in addition, glaucoma. Global developmental delay was observed in one child. All the children, except one, died during early childhood. Whole exome sequencing and whole genome sequencing did not reveal any other plausible variant. We provide further evidence that implicates PPP1R13L in a variable syndromic form of severe childhood-onset DCM and suggests expanding the spectrum of this condition to include glaucoma. Given the variability of the phenotype associated with PPP1R13-related DCM, a thorough evaluation of each case is highly recommended even in the presence of an apparently isolated DCM.

A novel homozygous SCN5A variant detected in sick sinus syndrome.

Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been reported in SSS, however, homozygosity of SCN5A is exceedingly rare. Here, we report a consanguineous family with four affected children with SSS. Symptomatic bradycardia necessitated implanting a pacemaker in all of them. Sequencing SCN5A revealed a novel homozygous variant (p.Cys1850Arg), which was predicted to interfere with protein folding. Our report describes the phenotype of a novel homozygous SCN5A variant and contributes to the compendium of molecular pathology of inherited arrhythmias in consanguineous populations.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

Phenotypic variability in a series of four pediatric patients with Andersen-Tawil syndrome: A Saudi experience.

Andersen-Tawil syndrome (ATS) is a rare genetic disorder characterized by periodic paralysis, ventricular arrhythmia, and dysmorphic features. However, the classical features are not always seen in the syndrome; therefore, the diagnosis can be challenging. We describe our experience with ATS in Riyadh, Saudi Arabia, by presenting a case series involving four patients in the pediatric cardiology clinic confirmed to have ATS. Despite the diversity in phenotypes and clinical course among the four cases, all patients had bidirectional ventricular tachycardia and were confirmed to have ATS by performing genetic testing. In this case series, we identified one novel and three previously described KCNJ2 mutations. We also confirmed the beneficial effect of AAI pacing in one of our patients, together with medical therapy with ß-blockers and flecainide. In Saudi Arabia, there is a distinct genetic pool and a high incidence of inherited diseases. Raising awareness about these diseases is crucial, especially in a country such as Saudi Arabia, wherein consanguinity remains a significant factor leading to an increased incidence of inherited diseases. Furthermore, because of the limited information available regarding this rare syndrome, we believe that this case series would offer an opportunity to provide a better understanding of ATS in our local region and worldwide.

The phenotype, genotype, and outcome of infantile-onset Pompe disease in 18 Saudi patients.

Infantile-Onset Pompe Disease (IOPD) is an autosomal recessive disorder of glycogen metabolism resulting from deficiency of the lysosomal hydrolase acid α-glucosidase encoded by GAA gene. Affected infants present before the age of 12 months with hypotonia, muscle weakness, and hypertrophic cardiomyopathy. Enzyme replacement therapy (ERT) has been shown to improve survival, cardiac mass, and motor skills. In this work, we aim to illustrate the genotypes of IOPD and the outcome of ERT in our population. The medical records of infants with confirmed diagnosis of IOPD who received ERT were reviewed. Eighteen infants (7 males, 11 females) were included in the study. The median age at presentation was 2 months and the median age at the start of ERT was 4.5 months. Fifteen (83.3%) infants died with a median age at death of 12 months. The 3 alive infants (whose current ages are 6½â€¯years, 6 years, and 10 years), who were initiated on ERT at the age of 3 weeks, 5 months, and 8 months respectively, has had variable response with requirement of assisted ventilation in one child and tracheostomy in another child. All infants were homozygous for GAA mutations except one infant who was compound heterozygous. All infants (n = 8) with truncating mutations died. Our work provides insight into the correlation of genotypes and outcome of ERT in IOPD in Saudi Arabia. Our data suggest that early detection of cases, through newborn screening, and immunomodulation before the initiation of ERT may improve the outcome of ERT in Saudi infants with IOPD.

Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity.

BACKGROUND: Congenital long QT syndrome (LQTS) is an inherited, potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70%, with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: To describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population. METHODS: Fifty-six Saudi families with LQTS were consecutively recruited and evaluated. Sequencing of KCNQ1, KCNH2, and SCN5A genes was conducted on all probands, followed by screening of family relatives. RESULTS: Genetic analysis was positive in 32 (57.2%) families, with mutations in KCNQ1 identified in 28 families (50%). Surprisingly, 17 (53.1%) probands were segregating homozygous mutations. Family screening identified 123 individuals with mutations; 89 (72.4%) were heterozygous, 23 (18.7%) were homozygous, and 11 (8.9%) were compound heterozygous. Compared to heterozygous, the phenotype was more severe in homozygous individuals, with cardiac symptoms in 78.3% (vs 12.4%), family history of sudden death in 64.7% (vs 44.4%), and prolonged QT interval in 100% (vs 43.8%). Congenital deafness was found in 11 (47.8%) homozygous probands. CONCLUSION: Our study provides insight into the clinical and molecular profiles of LQTS in a consanguineous population. It underscores the importance of preemptive management in homozygous patients with LQTS and the value of clinical and molecular screening of at-risk relatives.

Polymorphisms in RAD51 and their relation with breast cancer in Saudi females.

The present study aimed at investigating the relationship between rs1801320 (G>C), rs1801321 (G>T), and rs2619681 (C>T) RAD51 gene polymorphisms and the risk of breast cancer development in Saudi females. The genotypes were analyzed using TaqMan genotyping assay and polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele frequencies were computed using chi-square or Fisher's exact test (two-tailed) by SPSS 21 software. The results showed that rs1801321G>T GG genotype and G allele frequency were strongly (P<0.0001) related to an elevated risk of breast cancer, while the mutant T allele appeared to provide protection against breast cancer development as observed from the significantly lower (P<0.0001) frequencies of the TT and GT genotypes in cancer patients compared to the healthy controls. The variant rs1801320G>C showed no significant differences in the frequencies of the genotypes and alleles in the patients and the control groups. The CC genotype and C allele frequency of rs2619681 (C>T) variant were significantly (P=0.012) higher in cancer patients, whereas the T allele showed a protective effect against cancer development. The frequencies of the three single-nucleotide polymorphisms did not differ in cancer patients with different tumor grades and human epidermal growth factor receptor 2 status (+ or -). However, the genotype frequency of rs1801320 (135G>C) differed in the patients with estrogen receptor (ER)+ and ER-, where CC genotype showed a significantly higher prevalence in the females with ER- who were suffering from breast cancer. In addition, the frequency of C allele of rs2619681 (C>T) was also significantly higher in the breast cancer patients who were ER+ and progesterone receptor (PR)+ compared to those with ER- and PR-. In the Saudi females, rs1801320 did not show an association with risk of breast cancer. Taken together, the results suggest that RAD51 rs1801321 polymorphism may be involved in the etiology of breast cancer in the Saudi females; however, further studies are necessary to confirm this relation.

A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy.

BACKGROUND: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM. METHODS: In a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect. RESULTS: A region of homozygosity (ROH) on chromosome 8q24.13-24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative. CONCLUSIONS: Our data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy.

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.

BACKGROUND: There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families. METHODS: Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients. RESULTS: We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres. CONCLUSIONS: Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

The phenotype of a CASQ2 mutation in a Saudi family with catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) manifests with episodic syncope or sudden death in young patients following physical activity or emotional stress. The autosomal recessive form of CPVT is caused by mutations in the CASQ2 gene. In a consanguineous family, a novel homozygous CASQ2 mutation (p.L77P) was identified in a child with CPVT who required implantation of a cardioverter defibrillator due to episodes of syncope while on medical therapy. Genetic testing found the younger sibling, who had normal initial clinical screening, to be affected. Our cases underscore the importance of family screening through genetic testing to preemptively apply the appropriate medical intervention in CPVT.

Identification of a novel IVD mutation in a consanguineous family with isovaleric acidemia.

Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by a deficiency of isovaleryl-CoA dehydrogenase encoded by IVD gene. In this case study we report the first Saudi IVA patients from a consanguineous family with a novel transversion (p.G362V) and briefly discuss likely phenotype-genotype correlation of the disease in the Saudi population. We explored the functional consequences of the mutation by using various bioinformatics prediction algorithms and discussed the likely mechanism of the disease caused by the mutation.

Recessively inherited severe aortic aneurysm caused by mutated EFEMP2.

Familial aortic aneurysm (AA) is mostly inherited as an autosomal dominant disorder. However, recessively inherited AA has also been observed but in association with skin manifestations of cutis laxa, which is caused by a mutated EFEMP2 gene. In the present study, we recruited 9 patients, from 4 unrelated consanguineous families, with recessively inherited AA. The index cases, their parents, and siblings underwent clinical evaluation and cardiac imaging. In the affected subjects, the clinical presentation ranged from sweating and cyanosis at 3 months of age to incidental findings in an asymptomatic adult. The echocardiogram revealed a wide spectrum of severity of the AA, with a Z-score varying from 5 to 33. Intrafamilial variability was also evident; 2 unrelated subjects were detected at 17 and 20 years of age through family screening. The skin manifestations of cutis laxa were not found in any patient. In 1 family, genome-wide single-nucleotide polymorphism analysis detected a homozygous block, shared by 2 affected siblings, on chromosome 11 at q13. Sequence analysis of EFEMP2, located on chromosome 11 at q13, identified a novel homozygous mutation (p.E161K) in all 9 affected subjects. In this largest cohort of reported patients with a mutated EFEMP2 gene, we illustrate the phenotypic spectrum of inherited AA due to a novel EFEMP2 mutation. In conclusion, our work suggests that in families with apparently recessively inherited AA, molecular analysis of EFEMP2 gene might be warranted.