Ahmed Bouhouche

There is considerable variability in the clinical presentation of COVID‐19 among patients infected with SARS‐CoV‐2. Genome‐wide association studies (GWASs) have identified the 12q24.13 and 3p21.31 regions, derived from Neanderthal DNA, as the human genetic loci most strongly associated with COVID‐19 severity. We examined in this study the 3p locus in the Moroccan population by analysing allele and haplotype frequencies at the LZTFL1 gene and their associations with COVID‐19 outcomes. Three SNPs at LZTFL1 , tagging the Neanderthal‐derived COVID‐19 risk haplotype, were sequenced by Sanger's method in 102 ambulatory participants and 105 hospitalized patients and have been compared to 118 controls negative for SARS‐CoV‐2 infection using logistic regression analysis. Results showed that the prevalence of the lead variant rs11385942 in this locus was 8.9%, whereas the variants rs35044562 and rs13078854, which tag the Neanderthal haplotype, were present in only 6.3%. Our study showed that only the rs35044562‐T and rs13078854‐A alleles were associated with a 2.5‐fold increased risk of severe COVID‐19 ( p = 0.028). These two alleles, in LD with the rs11385942‐AA one, form the haplotype inherited from the Neanderthal, the only haplotype associated with COVID‐19 severity in the Moroccan population ( p = 0.030), whereas sub‐Saharan African and the rare local haplotype also containing the rs11385942 variant do not influence the COVID‐19 outcomes 19 ( p > 0.05). Furthermore, our study showed that the Neanderthal haplotype at 3p21 locus exists in the inhabitants of Morocco at a frequency close to that of Europeans and suggests a close connection between North Africa and Eurasia.

A 29-year-old woman with a novel homozygous VPS13A frameshift variant presented with drug-resistant temporal-lobe epilepsy and severe sensory neuronopathy, but no acanthocytes on repeated blood smear...

Background: Parkinson’s disease (PD), although widely heterogeneous and manifesting with numerous motor and non-motor symptoms, presents clinically as a single entity worldwide. Its genetic causes are also heterogeneous and include highly penetrant variants in a single gene representing rare monogenic forms, and rare or common variants conferring a relative disease risk representing more frequent multigenic forms. Most of these variants have been discovered in patients of European ancestry. Since the genetic basis of PD can vary significantly between populations due to differences in allele frequencies, little is known about the genetics of PD in other populations, particularly from Africa. Morocco, located in a region of North Africa, constitutes a subcontinent known for a weak external genetic influence and for a local genetic continuity for millennia, which makes it a region of interest to study the genetic causes of PD. Summary: This review aimed to summarize published research data on the genetic profile of PD patients from the Moroccan population to describe its genetic architecture. Unlike in Western countries, PD in Morocco is predominantly a Mendelian disease reaching up to 50%, due to the high prevalence of the LRRK2 G2019S dominant variant and to relatively less frequent PRKN and PINK1 recessive variants due to the high rate of consanguinity. Additionally, rare high-risk variants in LRRK2, VPS13C, MAPT, and POLG, in oligo- or polygenic ways, may contribute to increasing the genetic risk of the disease. Key Messages: We, therefore, show that the genetic architecture of PD in Morocco, a country in the subcontinent of North Africa, was different from that of sub-Saharan Africa and the rest of the world. This will help improve diagnostic accuracy, subdivide the clinical variability of the disease into groups of common genetic and biological causes for a better therapeutic management strategy, and test molecules from ongoing clinical trials.

REVIEW COMMENTS Guella et al. present a study on the association of ABO groups with COVID-19 outcomes in the AUE population. The paper was poorly documented and poorly written, and all sections were very short. So it does not reach the level require...

Introduction: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely among affected individuals, ranging from isolated hematuria to end-stage renal disease. The genetic causes of AS primarily involve mutations in the genes encoding type IV collagen COL4A3, COL4A4, and COL4A5, which play essential roles in maintaining the structural integrity of the glomerular basement membrane in the kidney, the cochlea, and the retina. They can be transmitted in autosomal dominant, autosomal recessive, and X-linked recessive. Case Presentation: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the COL4A3 gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. Conclusion: We report a novel nonsense pathogenic variant in COL4A3 that expends the allelic spectrum in AS. Clinical exploration and genetic testing of all the family members revealed intrafamilial clinical variability, suggesting a pseudo-dominant inheritance and a reduced penetrance.

Background: Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. Methods: The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. Results: Two homozygous variants in the WFS1 gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by in silico tools and molecular modeling. Conclusion: Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.

Infection by the recent SARS-CoV-2 virus causes the COVID-19 disease with variable clinical manifestations ranging from asymptomatic or mild respiratory symptoms to severe respiratory distress and multiorgan failure. The renin-angiotensin system, responsible for maintaining homeostasis and governing several critical processes, has been considered the main system involved in the pathogenesis and progression of COVID-19. Here, we aimed to assess the possible association between variants in the RAS-related genes and COVID-19 susceptibility and severity in a sample of the Moroccan population. A total of 325 individuals were recruited in this study, with 102 outpatients, 105 hospitalized patients, and 118 healthy controls negative for SARS-CoV-2 infection, and subjected to NGS gene panel sequencing containing eleven RAS pathway genes. A total of 65 functional variants were identified, including 63 missenses, 1 splice, and 1 INDEL. Most of them were rare, with 47 (72%) found in a single individual. According to the common disease/common variant hypothesis, five common candidate variants with MAF > 10% were identified (ACE2 rs2285666, TMPRSS2 rs12329760, AGT rs699 genes, ACE rs4341, and ACE rs4343). Statistical analysis showed that the ACE rs4343 AA genotype was associated with a 2.5-fold increased risk of severe COVID-19 (p = 0.026), and the T genotype of the ACE2 rs2285666 variant showed a borderline association with susceptibility to SARS-CoV-2 in males (p = 0.097). In conclusion, our results showed that the RAS pathway genes are highly conserved among Moroccans, and most of the identified variants are rare. Among the common variants, the ACE rs4343 polymorphism would lead to a genetic predisposition for severe COVID-19.