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Background At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all “solved” cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received “negative” clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.

Purpose Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. Methods Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. Results In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes ( BBIP1 , MAPKBP1 , PDE6D , and WDPCP ), and propose nine novel candidate genes ( CCDC67 , CCDC96 , CCDC172 , CEP295 , FAM166B , LRRC34 , TMEM17 , TTC6 , and TTC23 ), three of which ( LRRC34 , TTC6 , and TTC23 ) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19 -related Stargardt disease and SCLT1 - and CEP164 -related Bardet–Biedl syndrome. Conclusion In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

Background Graves’ disease is the autoimmune activation of the thyroid gland causing diffuse enlargement and hyperfunction of the gland. Manifestations of Graves’ disease are multisystemic and include thyroid orbitopathy; pretibial myxedema, also referred to as thyroid dermopathy; and thyroid acropachy, described as a severe form of thyroid dermopathy. Our paper focuses on an atypical case of thyroid dermopathy. Case presentation An 11-year-old Saudi male presented with a prominent diffuse goiter and exophthalmos. Investigations were consistent with a diagnosis of Graves’ disease. The physical exam showed diffuse, non-pitting swelling of the ankle and penis, mimicking a lymphatic malformation. Further, multiple nodules were found on the hands and feet. Treatment of the nodules with cautery resulted in more severe nodules. Conclusion This report describes rare presentations of thyroid dermopathy mimicking lymphatic malformation. The Koebner phenomenon can explain this patient’s atypical presentations. Intralesional injections of triamcinolone and total thyroidectomy showed clear improvement.

Background Congenital hyperinsulinism is a rare disorder characterized by inappropriate insulin secretion, leading to persistent hypoglycemia. One genetic subtype, hyperinsulinism–hyperammonemia syndrome, results from activating mutations in the GLUD1 gene. This study aimed to describe the clinical spectrum, genetic variants, and outcomes of patients with GLUD1-related hyperinsulinism–hyperammonemia syndrome treated at a tertiary care center in Saudi Arabia. Methods This retrospective case series included five patients of Saudi ethnicity diagnosed with GLUD1 -associated hyperinsulinism–hyperammonemia syndrome between September and November 2023 at King Faisal Specialist Hospital and Research Centre. Clinical, biochemical, imaging, and genetic data were collected from medical records. Descriptive statistics were used to summarize the findings. Results All five patients (four pediatric, one adult) presented with hypoglycemia, elevated insulin levels, and persistent hyperammonemia. Genetic testing confirmed GLUD1 mutations in all cases, with two patients sharing the c.1493C > T (p.Ser498Leu) variant. Diazoxide therapy effectively controlled hypoglycemia in most patients. Two patients experienced significant neurological complications, including seizures and developmental delay. One adult patient underwent pancreatectomy with improvement in hypoglycemia control but retained chronic neurological sequelae. Brain magnetic resonance imaging abnormalities and secondary genetic variants were identified in two cases. Conclusion GLUD1 -related hyperinsulinism–hyperammonemia syndrome presents with a wide clinical spectrum, often with early onset and risk of neurological impairment if not promptly treated. Early diagnosis and individualized management—including genetic testing and diazoxide therapy—are essential to prevent irreversible complications. Further multicenter studies are warranted to better understand long-term outcomes in affected populations.

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis. The mutation spectrum was analyzed by NGS in 55 Saudi patients with CH. The most common mutations were TG and TSHR. SLC26A7 appears to be associated with thyroid hormone synthesis.

Background Inappropriately high levels of insulin secretion can cause the potentially fatal condition of persistent hyperinsulinemic hypoglycemia of infancy. Our paper focuses on another cause of severe hypoglycemia, which can be easily missed. Case presentation An 18-month-old Saudi female was referred to our hospital for further investigation and management of her recurrent hypoglycemic attacks as a case of persistent hyperinsulinemic hypoglycemia of infancy. During admission, we noticed multiple red flags from the history; the mother was insisting on a pancreatectomy, rather than going for a positron emission tomography scan, and most importantly, all hypoglycemic attacks occurred while the mother was around. Consequently, after further investigation, the case was diagnosed as a caregiver-fabricated illness, and the case was referred to the Child Protection Center. Conclusions One must have a high index of suspicion to diagnose caregiver-fabricated illness. Physicians should be more attentive to prevent such a disease, which could eventually become lethal if left unnoticed.

Ehlers–Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6 , GORAB , ZNF469 , B3GAT3 , ALDH18A1 , FKBP14 , PYCR1 , CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1 . Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.

Steroidogenic acute regulatory (StAR) protein deficiency is a rare autosomal recessive disorder that disrupts steroid hormone biosynthesis, resulting in congenital adrenal hyperplasia (CAH) and variations in sexual development. However, limited data is available in Saudi Arabia. Therefore, this study describes the clinical and genetic findings of seven Saudi patients with StAR deficiency. This case series was conducted at King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, Saudi Arabia. All seven patients were born to consanguineous parents, most commonly first cousins. Five patients had a 46,XY karyotype, and two had a 46,XX karyotype. All were clinically diagnosed with CAH due to StAR deficiency. Despite their chromosomal sex, all presented with a female external phenotype. Clinical features ranged from typical female genitalia to varying degrees of feminization with bilateral inguinal gonads or undescended testes in 46,XY individuals. Most patients exhibited electrolyte disturbances and chronic salt-wasting. Interestingly, two cases presented with neonatal cholestatic jaundice. Genetic testing confirmed homozygous pathogenic or likely pathogenic variants in all cases. Dysmorphism occurred in one patient with (c.402T >G, p.Tyr134Ter) mutation. The five 46,XY patients underwent bilateral gonadectomy. All patients remain clinically stable on long-term steroid replacement. This study highlights the diverse clinical spectrum of StAR deficiency, ranging from early adrenal crisis to DSD and atypical presentations such as cholestasis. The findings underscore the importance of early genetic diagnosis and counseling, particularly in consanguineous populations, and point to the need for continued research into the clinical and molecular complexity of StAR deficiency.

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.

Denys-Drash syndrome (DDS) is a rare genetic disorder characterized by mutations in the Wilms tumor suppressor gene ( ), leading to a triad of conditions including nephrotic syndrome progressing to end-stage renal disease (ESRD), Wilms tumor, and ambiguous genitalia. We present two pediatric cases illustrating the complexity and variability of DDS. The first case is a 7-month-old male presenting with ambiguous genitalia, nephropathy, and intussusception. Genetic analysis identified a likely pathogenic heterozygous variant: c.1384C >T (p.Gln462Ter). Despite surgical interventions, treatment was delayed due to COVID-19 restrictions, and the patient unfortunately passed away at 16 months during the lockdown period. The second case involves an 8-month-old female with normal external genitalia, a horseshoe kidney, bilateral renal masses, and recurrent hypotensive episodes. Genetic testing revealed a pathogenic heterozygous variant: c.453G >A (p.Trp151Ter). She was diagnosed with DDS-associated Wilms tumor and, despite aggressive management, passed away at 21 months. These cases underscore the importance of early diagnosis, multidisciplinary management, and personalized therapeutic approaches in DDS patients. Bilateral nephrectomy, renal transplantation, and monitoring for Wilms tumor are pivotal in improving prognosis, though variability in clinical presentations often complicates decision-making.