Exploring Splice-Site Mutations in LAMA2-Related Muscular Dystrophies: A Comprehensive Analysis of Genotypic and Phenotypic Patterns.

LAMA2-related muscular dystrophies (LAMA2-RDs) constitute the most prevalent subtype of congenital muscular dystrophies (CMDs). The clinical spectrum of LAMA2-RDs exhibits considerable diversity, particularly in motor development and disease progression. Phenotypic variability ranges from severe, early-onset presentation, known as merosin-deficient CMD type 1A, to milder, late-onset presentations, including limb-girdle muscular dystrophy-like phenotype. In this study, whole exome sequencing (WES) was applied to a family with a single proband affected by severe muscular dystrophy. The identified causative mutation was a biallelic splice-site mutation in intron 58 of the LAMA2 gene, leading to a premature termination codon in the critical G domain of laminin-α2 and resulting in a severe phenotype. Additionally, we summarized previously reported splice-site mutations to investigate the clinical and transcription consequences of these mutations. Our findings conclude that splice-site mutations predominantly lead to severe MDC1A, whether in a homozygous or heterozygous state, often associated with another loss-of-function mutation. Besides, splice-site mutations with available analysis of their transcriptional consequences were found to be responsible for exon skipping in most cases and the loss of the reading frame. These findings revealed the importance of WES in identifying disease-causing mutations, particularly in highly diversified pathologies like LAMA2-RDs. The results also underscore the importance of transcriptional analysis in determining the impact of splice-site mutations and the phenotype of LAMA2-RDs on patients.

Autosomal Dominant Intellectual Development Disorder-6 (MRD6) Without Seizures Linked to a De Novo Mutation in the grin2b Gene Revealed by Exome Sequencing: A Case Report of a Moroccan Child.

Autosomal dominant intellectual development disorder-6 (MRD6) arises from a grin2b gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive disabilities, seizures, muscle tone decline, and autism-like traits. Its severity ranges from mild impairment to severe epilepsy. The disorder's rarity is emphasized by roughly 100 reported GRIN2B-related cases, spotlighting the gene's significance in brain development. We present the case of a three-year-old Moroccan boy who was referred to a neuropediatric department for a molecular diagnosis. Initial genetic testing yielded inconclusive results, and subsequent tests for Angelman syndrome and metabolic diseases showed no abnormalities. Given the complexity of the disorder, exome sequencing was employed to identify the underlying genetic cause. Exome sequencing identified a nonsense (STOP) mutation c.3912C>G (p.Tyr1304Ter) in the grin2b gene in the heterozygous state known to be present in MRD6 (Online Mendelian Inheritance in Man (OMIM) 613970). The family segregation study shows that this is a de novo variant, which is confirmed by Sanger sequencing. This variant has not been previously reported in the GnomAD database. Based on current scientific knowledge, the variant is considered pathogenic (PVS1, PS2, PM2, PP3, PP5) according to the criteria of the American College of Medical Genetics and Genomics (ACMG). The mutation in the grin2b gene (p.Tyr1304Ter) was predicted to be deleterious through bioinformatics analysis tools. This study highlights the crucial role of the grin2b gene in normal brain development and communication within the nervous system. It also sheds light on the impact of a novel genetic mutation, identified through exome sequencing, on causing an intellectual developmental disorder in a child patient from Morocco.

Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families.

Background: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance. To offer an adequate patient management and therapeutic treatment for MODY patients, in addition to an early efficient diagnosis of their asymptomatic relatives, it is crucial to set an accurate molecular diagnosis. Hence, our aim was to determine the frequency of HNF1A and GCK genes among Moroccan-suspected MODY patients. Methods: Twenty suspected MODY patients were screened for HNF1A and GCK mutations using Sanger sequencing and MLPA methods. Segregation analysis of identified mutations was performed among family members. The pathogenic nature of missense variants was predicted using bioinformatic tools. Results: A total of two mutations were revealed among all patients raising the diagnostic rate to 10%. We identified a large novel GCK deletion (c.209-?_1398+?del) by MLPA in one patient and a previously reported missense substitution (c.92G > A) in HNF1A gene. Conclusion: This is the first investigation to perform the molecular diagnosis of MODY suspected patients. Our findings constitute a primary contribution towards unraveling the genetic landscape involved in the pathogenesis of MODY disease in Morocco.

[Fanconi anemia at the University Hospital (CHU) Hassan II of Fez: about 6 cases]. / Anémie de fanconi au CHU Hassan II Fès: à propos de 6 observations.

Fanconi anemia is a recessive disorder associated with chromosomal instability. It is marked by phenotypical heterogeneity which includes medullary deficiency, a variable malformation syndrome, a predisposition to develop acute leukaemias myéloïdes (ALM) and a cellular over-sensitiveness with the agents bridging the ADN. The diagnosis is based on the abnormal increase in the rate of spontaneous breaks chromosomal but especially and in a specific way, on a clear increase in these chromosomal breaks in the presence of bifunctional alkylating agents, which is the case in our six patients. Genetic counseling is that available for autosomal recessive diseases. We report our initial observations conducted at the University Hospital (CHU) Hassan II of Fez confirmed by the detection of a large chromosomal instability after culture with Mitomycin C compared to a normal control group. The purpose of this study was to update our knowledge of Fanconi anemia genes and to highlight the role of cytogenetics in its diagnosis and the genetic counseling for better management of affected children and their families.