Consanguinity and Occurrence of Monogenic Diseases in a Single Tertiary Centre in Riyadh, Saudi Arabia: A 2 Years Cross-Sectional Study.

Background: Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population. Methods: Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022. Results: The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%). Conclusion: In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.

A Biallelic Variant in FRA10AC1 Is Associated With Neurodevelopmental Disorder and Growth Retardation.

Objectives: Our objective was to identify the genetic cause in a family with a remarkable history of neurodevelopmental disease and growth retardation. Methods: A neurologic evaluation was performed, and DNA samples were obtained from the affected siblings and parents to perform whole-exome sequencing (WES). Results: Both siblings presented with dysmorphic features, failure to thrive, global developmental delay, generalized hypotonia, feeding problems, and congenital heart disease. WES revealed a homozygous nonsense variant in the FRA10AC1 gene in both siblings. Discussion: A recent study has reported the first association of biallelic variants in the spliceosomal C complex gene, FRA10AC1, with syndromic neurodevelopmental disease and growth retardation in 5 patients from 3 consanguineous families complex. In this study, we provide the first confirmation of the reported FRA10AC1-related neurologic syndrome in an additional family.

Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course.

WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here, two novel homozygous WIPI2 variants [c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)] were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harbouring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.

Expanding the KIF4A-associated phenotype.

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.

Epilepsy, neuropsychiatric phenotypes, neuroimaging findings, and genotype-neurophenotype correlation in 22q11.2 deletion syndrome.

OBJECTIVE: To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype. METHODS: We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed RESULTS: Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype. CONCLUSION: 22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X-linked trichothiodystrophy.

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.

Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy.

Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.