Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.

Woodhouse‐Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in theDCAF17gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in theDCAF17gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.

Background: Newborn screening is an essential public health strategy that aims to detect a range of conditions, including inborn errors of metabolism, in neonates shortly after birth. The timely identification is crucial due to the asymptomatic nature of many conditions at birth, but which can lead to significant health complications if left untreated. Through this study, we aimed to investigate the incidence of IEMs screened by the Qatar National Newborn Screening Program. Methods: We retrospectively analyzed a total of 351,223 newborns screened from 2010 to 2023. The incidence for the studied IEMs was calculated and correlated with demographics, consanguinity, and family history. In addition, the diagnostic yield of different tests utilized was assessed. Results: Our study revealed a total of 318 positive cases with IEMs, and a significantly high incidence of 1:1105 for IEMs in Qatar. Classical Homocystinuria was the most frequently detected condition, with a cumulative incidence of 1:6754 live births, linked to the founder variant p. Arg336Cys in the CBS gene. Aminoacidopathies were the most prevalent category, followed by fatty acid oxidation disorders, organic acidurias, biotinidase deficiency, and urea cycle disorders. Genetic testing showed a high diagnostic yield of 90%. Of the 60 cases that underwent targeted variant testing, 98% were confirmed, while 90% of the 59 cases tested by single gene testing were confirmed. Conclusions: Our study provides the incidence rates of IEMs in Qatar and novel insights that could facilitate setting up/developing IEM incidence-reducing strategies and improving outcomes for affected newborns and their families.

Non-syndromic Inherited Retinal Dystrophies (IRDs) are a set of degenerative retinal diseases that vary clinically and genetically, including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). IRDs are a significant cause of vision loss in young adults globally. To date, more than 280 genes have been associated with IRD pathogenesis. This study aims to investigate the genetic basis of non-syndromic IRD in the Qatari population and to assess the diagnostic yield of various genetic tests through a retrospective cohort study. Our study identified 49 eligible patients with IRD, 61.2% of whom were Qatari. Rod-dominated phenotypes accounted for 51% of the hereditary retinal diseases in this cohort. Whole-exome sequencing with mitochondrial genome testing (WES Plus) was the most frequently utilized genetic test. A total of 55 variants were identified across 32 IRD-associated genes. Of the 49 cases, 34 (69.4%) were initially classified as solved, and an additional five were likely to be solved based on familial segregation analysis. Variants in the ABCA4 gene were the most commonly observed, present in eight patients, with the c.5882G>A variant being the most recurrent, identified in three of these cases. Specific genes exhibited recurrent variations, including pan-ethnic variants that are common across multiple populations. These variants merit prioritization in testing due to their global prevalence. WES is recommended as a first-tier test for non-syndromic IRD cases, as it accelerates diagnosis, facilitates earlier interventions, and provides a comprehensive genetic picture by incorporating information from family members. Moreover, our study highlighted the significance of performing family segregation analyses in identifying possible causative variants. This is the first genetic study of IRD in Qatar, laying the groundwork for further research on the epidemiology and genetics of non-syndromic IRD in this understudied region.