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Inborn errors of metabolism (IEM) and endocrine disorders are common genetic conditions in the Saudi population with the incidence rate often underestimated. Newborn screening (NBS) using various disease panels provides the first line in the early detection and intervention among infants with a high risk of IEM. Here we aim to assess the incidence of screening disorders and provide an overview of the NBS program at the Ministry of Health Tertiary Care King Fahad Medical City. Dried blood spots (DBS) from 40,965 newborn infants collected on the second day after birth were analyzed for 20 disorders. The total number of positive screen (“repeat”) samples over 10 years was about 1% (n = 382/40,965). The true positive result rate was 15.3% (n = 46/301) with the recall rates of individual disorders ranging from 0.26% (95% CI, 0.17–0.69) to 2.6% (95% CI, 2.19–3.05). The false positive result rate was 84.7% (n = 255/301) with biotinidase activity found to be the most common cause of the second sample repeat. The overall incidence of the screened diseases was 1:891 (95% CI, 11.61–12.47). CH and CAH are the most prevalent among endocrine disorders with an incidence of 1:4097 (95% CI, 2.19–3.05), and PA and ASA among the IEM with an incidence of 1:10,241 (95% CI, 0.09–0.95). In summary, we provide updated data and our experience on the incidence of various IEM and endocrine disorders among the Saudi population, highlight the role of false positive results of biotinidase activity that can increase the recall rate and lead to overestimation of the incidence data, and recommend multicenter studies to achieve a successful national NBS program.

Pseudohypoaldosteronism type 1 (PHA1) is an autosomal-recessive disorder characterized by defective regulation of body sodium (Na) levels. The abnormality results from mutations in the genes encoding subunits of the epithelial Na channel. Patients with PHA1 present in infancy as being in adrenal crisis. A 41-day-old female who presented with recurrent adrenal crisis did not adequately respond to hydrocortisone and required mineralocorticoid therapy. The patient’s demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and for use in genetic studies. Bidirectional Sanger sequencing of was conducted. The entire coding region of 12 exons and 20 bp of flanking intron were sequenced. Genetic analyses revealed a new mutation - c.729_730delAG (p.Val245Glyfs*65) - in exon four. Adrenal crisis during the neonatal period highlights the importance of early screening for PHA1. Genetic testing could help to anticipate the prognosis, severity, onset of the disease, and the mode of inheritance, especially given its extensive phenotype.

 DExH-Box Helicase 30 (DHX30) is a gene that codes for proteins. It belongs to the class of RNA secondary structure unwinding helicases known as DExH-boxes. There have been numerous reports of pathogenic DHX30 variants. Most mutations, but not all, result in severe phenotypic abnormalities. The most common symptoms are severe motor developmental delay, intellectual disability, sleep disturbances, autism spectrum disorder, seizures, and gait abnormalities. The objectives of reporting this case are: To report a novel mutation giving rise to NEDMIAL and to update the literature regarding the manifestation of the case of a rare condition (NEDMIAL).  We report the case of a 12-year-old female who presented with similar complaints of severe motor impairment, seizures, intellectual disability, and absent language and was later diagnosed on Next-Generation Sequencing (NGS) with an autosomal dominant neurodevelopmental disorder (NEDMIAL).  We report a case of neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) with a De novo novel DHX30 mutation (p.Pro796Leu) detected by whole exome sequence. We suggest upgrading the variant classification of DHX30:p.Pro796Leu to likely pathogenic, according to the evidence found in our patient. To the best of our knowledge, this is the first reported case of this mutation and disorder in the Middle East.

To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. Detailed phenotyping and next-generation sequencing (panel and exome). Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello–Carey syndrome–like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Background Clinical exome and genome sequencing has transformed the diagnostic workup of patients with genetic disorders. The extensive body of evidence supporting the application of this clinical genomics approach in pediatric patients stands in stark contrast to the relative paucity of evidence for its use in the adult population. Here, we describe the largest cohort to date of adult patients who underwent clinical exome and genome sequencing for suspected genetic diagnoses. Methods A total of 2763 adult patients (2529 families) from all regions of Saudi Arabia are included in this cohort (2202 exomes, and 561 genomes). Results The diagnostic rate is 38.9% spanning 535 Mendelian genes and revealing clinical diagnostic errors in 38% of patients with positive reports. Structured feedback using C-GUIDE demonstrates clinical utility in 90% of positive cases. Consistent with the highly consanguineous nature of the local population, the majority (61%) of diagnosed phenotypes are recessive (94.6% homozygous) and founder variants account for 85% (414/487) of these variants. The same population characteristic has also led to the encounter of extremely rare, even novel recessive disorders including a highly penetrant novel RNF43 -related hemochromatosis, NFXL1 -related syndrome of hyperlaxity, short stature, and kidney disease, as well as autosomal recessive forms of typically dominant disorders. Multilocus phenotypes are observed in 5% of cases although only 26.7% of these are caused by two recessive variants. That 70% of molecular diagnoses encountered in our cohort are typically described in pediatric patients allowed us to observe highly unusual clinical presentations in the adult population. This delayed diagnosis also represents a missed opportunity for effective treatment in many instances and we note the availability of treatment for 26% of diagnosed conditions. Of particular interest are patients with monogenic disorders that could be overlooked as common multifactorial adult diseases (e.g., diabetes, dyslipidemia, stroke, chronic kidney disease, and dementia). Finally, we note the opportunities of deploying adult clinical genomics in an underrepresented population where 45.5% (373/819) of encountered variants are completely absent in gnomAD. Conclusions Our results illustrate numerous benefits of a clinical genomics approach in adult medicine and argue for a broader implementation than currently practiced.

Rabson-Mendenhall syndrome (RMS) is a rare genetic condition marked by severe insulin resistance, leading to persistent hyperglycemia that can sometimes be misdiagnosed as type 1 diabetes mellitus (T1DM). This case report details a 34-year-old male who was referred to a tertiary center for genetic evaluation to rule out insulin resistance syndrome. The patient had been diagnosed with T1DM since childhood, struggling to control his hyperglycemia despite high doses of insulin. Physical examination revealed acanthosis nigricans, prognathism, and other dysmorphic features. Genetic testing identified pathogenic variants in the insulin receptor (INSR) gene, confirming the diagnosis of RMS. Insulin resistance syndromes are prone to misdiagnosis, so a thorough patient history and careful physical examination are essential in distinguishing T1DM from insulin resistance syndrome. This is the first documented case of RMS in Saudi Arabia, and we emphasize the clinical findings and genetic confirmation in this patient.