The perception of genetic diseases and premarital screening tests in the central region of Saudi Arabia.

The prevalence of consanguineous marriages (CMs) varies worldwide from one country to another. However, the Middle East stands out as a region with a notably high rate of CMs. CM is particularly widespread in Saudi Arabia, where the prevalence of autosomal recessive genetic diseases has increased. This study aims to identify the Saudi population's awareness of genetic diseases and premarital screening tests (PMSTs). It also seeks to understand couples' perceptions of genetic diseases before and after marriage and their attitudes towards PMSTs and genetic counselling (GC) in reducing the risk of CM. Through the administration of online questionnaires, this cross-sectional study surveyed 2,057 participants to assess their awareness of genetic diseases and their understanding of testing and preventive measures for inherited diseases. Descriptive analysis, nonparametric chi-square tests and logistic regressions were performed to assess the association of categorical responses. This study included 2,035 Saudi Arabian respondents. A significant correlation was found between positive family history and partner selection (p = 0.001), as well as between partnering within the same tribe (p = 0.000139), with a different tribe (p = 0.000138) and from another family (p = 0.000489). About 91.3% of participants expressed agreement regarding the need to enhance public awareness and knowledge concerning genetic disorders, while 87% agreed that increased government regulations are required to prevent the spread of genetic diseases in affected families. Despite increased awareness of genetic diseases and PMSTs, there appears to be a lack of understanding regarding the limitations of PMSTs. The persistently high rate of CM underscores the challenge of altering marriage customs. Further governmental efforts are required to promote awareness of alternative reproductive options, establish new regulations and expand screening programmes.

Efficacy of low dose nitisinone in the management of alkaptonuria.

AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5 years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2 mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500 µmol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500 µmol/L.

Breaking new ground: Exploring de novo chromosomal rearrangements in 1p36 microdeletion.

Chromosomal structural variations (SVs) are linked to a wide range of phenotypes and arise due to disruptions during DNA replication, which can affect gene function within the SV regions. This case report details a patient diagnosed with neurodevelopmental delay. Detailed investigation through array comparative genomic hybridization revealed two pathogenic SVs on chromosome 1, which align with a 1p36 microdeletion, and a microduplication at 2p35.3, the latter being classified as a variant of unknown significance. The patient's clinical presentation is consistent with the 1p36 deletion syndrome, characterized by specific developmental delays and physical anomalies. Further genetic analysis suggests that these terminal rearrangements might stem from an unbalanced translocation between the short arms of chromosomes 1 and 2. This case underscores the complexity of interpreting multiple concurrent SVs and their cumulative effect on phenotype. Ongoing research into such chromosomal abnormalities will enhance our understanding of their clinical manifestations and guide more targeted therapeutic strategies.

Reclassifying variations of unknown significance in diseases affecting Saudi Arabia's population reveal new associations.

Introduction: Physicians face diagnostic dilemmas upon reports indicating disease variants of unknown significance (VUS). The most puzzling cases are patients with rare diseases, where finding another matched genotype and phenotype to associate their results is challenging. This study aims to prove the value of updating patient files with new classifications, potentially leading to better assessment and prevention. Methodology: We recruited retrospective phenotypic and genotypic data from King Saud Medical City, Riyadh, Kingdom of Saudi Arabia. Between September 2020 and December 2021, 1,080 patients' genetic profiles were tested in a College of American Pathologists accredited laboratory. We excluded all confirmed pathogenic variants, likely pathogenic variants and copy number variations. Finally, we further reclassified 194 VUS using different local and global databases, employing in silico prediction to justify the phenotype-genotype association. Results: Of the 194 VUS, 90 remained VUS, and the other 104 were reclassified as follows: 16 pathogenic, 49 likely pathogenic, nine benign, and 30 likely benign. Moreover, most of these variants had never been observed in other local or international databases. Conclusion: Reclassifying the VUS adds value to understanding the causality of the phenotype if it has been reported in another family or population. The healthcare system should establish guidelines for re-evaluating VUS, and upgrading VUS should reflect on individual/family risks and management strategies.

Prospect of genetic disorders in Saudi Arabia.

Introduction: Rare diseases (RDs) create a massive burden for governments and families because sufferers of these diseases are required to undergo long-term treatment or rehabilitation to maintain a normal life. In Saudi Arabia (SA), the prevalence of RDs is high as a result of cultural and socio-economic factors. This study, however, aims to shed light on the genetic component of the prevalence of RDs in SA. Methodology: A retrospective study was conducted between September 2020 and December 2021 at King Saud Medical City, a tertiary hospital of the Ministry of Health (MOH), SA. A total of 1080 individuals with 544 potentially relevant variants were included. The index was 738, and the samples were tested in a commercialized laboratory using different molecular techniques, including next-generation sequencing. Result: A total of 867 molecular genetics tests were conducted on 738 probands. These tests included 610 exome sequencing (ES) tests, four genome sequencing (GS) tests, 82 molecular panels, 106 single nucleotide polymorphism (SNP) array, four methylation studies, 58 single-gene studies and three mitochondrial genome sequencing tests. The diagnostic yield among molecular genetics studies was 41.8% in ES, 24% in panels, 12% in SNP array and 24% in single gene studies. The majority of the identified potential variants (68%) were single nucleotide variants (SNV). Other ascertained variants included frameshift (11%), deletion (10%), duplication (5%), splicing (9%), in-frame deletion (3%) and indels (1%). The rate of positive consanguinity was 56%, and the autosomal recessive accounted for 54%. We found a significant correlation between the ES detection rate and positive consanguinity. We illustrated the presence of rare treatable conditions in DNAJC12, SLC19A3, and ALDH7A1, and the presence of the founder effect variant in SKIC2. Neurodevelopmental disorders were the main phenotype for which genetics studies were required (35.7%). Conclusion: This is the sixth-largest local study reporting next-generation sequencing. The results indicate the influence of consanguineous marriages on genetic disease and the burden it causes for the Kingdom of SA. This study highlights the need to enrich our society's knowledge of genetic disorders. We recommend utilising ES as a first-tier test to establish genetic diagnosis in a highly consanguineous population.

Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome.

Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy. Three genes, BUB1B, CEP57 and TRIP13, are involved in this syndrome. Only 7 patients carrying pathogenic variants in CEP57 are reported to date. Here we report two adult brothers born to Moroccan related parents, who presented with intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, learning disabilities, skeletal anomalies with thumb hypoplasia and dental abnormalities. Both brothers have mosaic variegated aneuploidies on blood karyotype. A previously reported homozygous 11 bp duplication was identified in CEP57 in the two brothers. We propose that a FoSTeS (Fork Stalling and Template Switching) mechanism could be involved in the occurrence of this duplication. This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly.

Postnatal clinical phenotype of five patients with Pallister-Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. METHODS: Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. RESULTS: Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. CONCLUSION: Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.