Impact of Deletion on Angelman Syndrome Phenotype Variability: Phenotype-Genotype Correlation in 97 Patients with Motor Developmental Delay.

Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype-phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures ( p = 0.04), ataxia ( p = 0.0008), and abnormal electroencephalogram (EEG) profile ( p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype-phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.

Unraveling the Diversity of GJB2 Mutations in Nonsyndromic Hearing Loss: A Comprehensive Study in the Moroccan Population.

INTRODUCTION: Despite the high genetic heterogeneity of hearing loss, mutations in the GJB2 gene are a major cause of autosomal recessive nonsyndromic hearing loss (NSHL) worldwide. However, the mutation profile of GJB2 in NSHL is under-investigated in Morocco, especially among simplex cases. This study aimed to identify the spectrum and frequency of GJB2 mutations in the Moroccan population among simplex and multiplex families with NSHL. METHODS: Moroccan families with NSHL were selected according to well-defined criteria. Selected families were screened for GJB2 gene variants using direct sequencing of the entire coding region of GJB2. RESULTS: A total of 145 affected individuals from 115 families with NSHL were included in this study (49 simplex, 66 multiplex). Mutations in the GJB2 gene were noted in 28.69% of the families (33/115), of which 75.75% were multiplex families and 24.24% were simplex. In total, seven different mutations were detected: c.35delG(p.G12fs), c.551G>A(p.R184Q), c.139G>T(p.E47X), c.109G>A(p.V37I), c.167delT(p.L56fs), c.617A>G(p.N206S), c.94C>T(p.R32C). The last three mutations have not previously been reported in Morocco. The most common GJB2 mutation was c.35delG (21.73%), followed by p.V37I (2.60%) and p.E47X (1.73%). CONCLUSIONS: Our study confirms a high prevalence of GJB2 variants in the Moroccan population, particularly the c.35delG mutation. Additionally, we have identified previously unreported or rarely reported mutations, revealing a greater diversity of GJB2 mutations. These findings emphasize the importance of comprehensive screening beyond the 35delG mutation for patients with NSHL, regardless of their family history. Integrating this approach into clinical care will enhance diagnosis and management of hearing loss in the Moroccan population.

Identification of novel and de novo variant in the SCN1A gene confirms Dravet syndrome in Moroccan child: a case report.

Dravet syndrome is a severe form of epilepsy characterised by recurrent seizures and cognitive impairment. It is mainly caused by variant in the SCN1A gene in 90% of cases, which codes for the α subunit of the voltage-gated sodium channel. In this study, we present one suspected case of Dravet syndrome in Moroccan child that underwent exome analysis and were confirmed by Sanger sequencing. The variant was identified in the SCN1A gene, and is a new variant that has never been described in the literature. The variant was found de nova in our case, indicating that it was not inherited from the parents. The variant, SCN1A c.965-2A>G p.(?), is located at the splice site and results in an unknown modification of the protein. This variant is considered pathogenic on the basis of previous studies. These results contribute to our knowledge of the SCN1A gene mutations associated with Dravet syndrome and underline the importance of genetic analysis in the diagnosis and confirmation of this disorder. Further studies are needed to better understand the functional consequences of this variant and its implications for therapeutic strategies in Dravet syndrome.

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.

FLT3 Mutations in Acute Myeloid Leukemia: Unraveling the Molecular Mechanisms and Implications for Targeted Therapies.

Acute myeloid leukemia (AML) is a heterogeneous and aggressive form of blood cancer characterized by the uncontrolled proliferation of myeloid precursor cells in the bone marrow. It affects individuals of all ages, with incidence increasing notably in those over 65 years old. Despite advancements in treatment, overall survival rates remain unsatisfactory, underscoring the need for a deeper understanding of the disease. Among the various genetic alterations implicated in AML pathogenesis, mutations in the FLT3 (Fms-like tyrosine kinase 3) gene have emerged as significant contributors to leukemogenesis. The FLT3 ​​​​​gene encodes a type III receptor tyrosine kinase crucial in regulating normal hematopoiesis. Approximately one-third of AML patients carry FLT3 mutations, making it one of the most frequently mutated genes in the disease. FLT3 mutations can be classified into internal tandem duplications (ITDs) and point mutations in the tyrosine kinase domain (TKD). FLT3 mutations are associated with adverse clinical features and are independent prognostic factors for poor overall survival and decreased remission rates in AML patients. Understanding the molecular mechanisms underlying FLT3 mutations in AML is critical for improving risk stratification, prognosis assessment, and the development of targeted therapies. By reviewing the current literature, this study aims to elucidate the functional consequences of FLT3 mutations in AML pathogenesis, explore the interaction of FLT3 signaling with other oncogenic pathways, and assess the prognostic significance of FLT3 mutations in clinical practice, providing information that can guide future research directions and facilitate the development of more effective therapeutic strategies.

A Case of Severe Teratozoospermia and Infertility Due to Homozygous Mutation c.144delC in the AURKC Gene.

This case report focuses on a 33-year-old male patient with a history of infertility, characterized by severe micro-oligo-asthenospermia. Subsequent analysis revealed the presence of multi-headed and multi-flagellated spermatozoa, indicating a potential case of macrocephalic spermatozoa syndrome linked to a mutation in the AURKC gene. Genetic testing confirmed the presence of a pathogenic mutation, c.144delC, in a homozygous state in the AURKC gene. The AURKC gene is known to play a vital role in meiosis during sperm production, and its mutation can lead to abnormalities in sperm morphology and function, resulting in conditions like macrozoospermia and male infertility. Additionally, the patient was diagnosed with a grade III varicocele on the left testicle, which further contributed to his infertility. Varicoceles are associated with decreased sperm production and quality, making them one of the common reversible causes of male infertility. This case highlights the significance of comprehensive diagnostic approaches, including spermogram, ultrasonography, and genetic testing, in managing male infertility cases. It also emphasizes the intricate interplay between genetic mutations and physical conditions in the manifestation of male infertility. Further research is warranted to elucidate the mechanisms underlying AURKC-related sperm abnormalities and to develop effective therapeutic interventions. Moreover, a deeper understanding of such genetic factors may aid in the development of genetic counseling strategies for couples experiencing infertility.

Genetic characterization of Schuurs-Hoeijmakers syndrome in a moroccan individual with heterozygote PACS1 mutation.

BACKGROUND: Schuurs-Hoeijmakers syndrome, an autosomal dominant neurodevelopmental genetic disorder, is a rare cause of intellectual disability (ID) affecting approximately 1 to 3% of all over the world. Only 87 cases have been recorded to date, and oddly enough, the majority of them share the same mutation (c.607 C > T; p.R203W). CASE PRESENTATION: This study presents the first reported case in Morocco of a 12-year-old female patient with PACS1 syndrome, identified during a cohort study of 24 patients with intellectual disability. The syndrome is caused by a de novo mutation of the PACS1 gene, located on chromosome 11, resulting in a single amino acid modification on the PACS1 protein. The abnormal protein disrupts cellular transport processes, leading to intellectual developmental delay, facial dysmorphia, and congenital anomalies. METHODS AND RESULTS: Exome sequencing was employed to identify the genetic mutation, and Sanger sequencing validated the presence of the recurrent mutation c.607 C > T (p.Arg203Trp) in the PACS1 gene. The mutation was found to be heterozygous and de novo, suggesting that it was not inherited from the patient's parents. Classification based on the American College of Medical Genetics and Genomics (ACMG) criteria confirmed its pathogenicity, with supporting evidence from bioinformatics analysis. The rarity of this variant in population databases further supports its pathogenic nature. CONCLUSION: This study expands our understanding of Schuurs-Hoeijmakers syndrome, a disorder with limited reported cases globally. The genetic heterogeneity of the disorder is highlighted, with the recurrent mutation being the most common pathogenic variant. Functional studies indicate the crucial role of PACS1 in craniofacial development and neurodevelopmental processes, with potential implications for autism spectrum disorders (ASD). Comprehensive genetic analyses are essential for accurate diagnosis and understanding the underlying causes of intellectual disabilities. Further research is warranted to unravel the mechanisms and potential therapeutic targets associated with PACS1-related neurodevelopmental disorders.

A homozygous missense variant in the PLCB4 gene causes severe phenotype of auriculocondylar syndrome type 2.

Auriculocondylar syndrome (ARCND) is a rare craniofacial birth defect characterized by malformations in the mandible and external ear (Question Mark Ear). Genetically, three distinct subtypes of ARCND (ARCND1, ARCND2, and ARCND3) have been identified. ARCND2 is linked to pathogenic variants in the PLCB4 gene (phospholipase C ß4). PLCB4 is a key effector of the EDN1-EDNRA pathway involved in craniofacial development via the induction, migration, and maintenance of neural crest cells. ARCND2 is typically inherited in an autosomal dominant pattern, with recessive inheritance pattern being rare. In this study, we report the first homozygous missense variant (NM_000933.4: c.2050G>A: p.(Gly684Arg)) in the PLCB4 gene causing ARCND in a 3-year-old patient with a severe clinical phenotype of the syndrome. The patient presented with typical craniofacial ARCND features, in addition to intestinal transit defect, macropenis, and hearing loss. These findings further delineate the phenotypic spectrum of ARCND associated with autosomal recessive PLCB4 loss of function variants. Notably, our results provide further evidence that these variants can result in a more severe and diverse manifestations of the syndrome. Clinicians should consider the rare features of this condition for better management of patients.

[Lynch syndrome: case report and review of the literature]. / Syndrome de Lynch: à propos d'un cas et revue de la litterature.

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancers. It increases cancer susceptibility, the risk of colorectal cancer in first-degree, endometrial cancer in women, and to a lesser extent, other cancers (ovarian, small bowel, stomach, urinary tract and hepatobiliary). Thus, the cumulative risk of developing colorectal cancer or endometrial cancer at the age of 80 years rises to 20 and 40% respectively. These cancers are characterized by a positive family history, their occurrence at an early age, and by the development of metachronous cancers in the same individual. This syndrome is transmitted in an autosomal dominant manner. The genes whose alteration is associated with the presence of an HNPCC belong to the family of DNA mismatch repair genes (DNA mismatch repair or MMR): MSH2, MLH1, and MSH6 are involved, in decreasing order of frequency, in 35%, 25% and 2% of cases respectively. Colonoscopic and gynecological monitoring is recommended for patients with a constitutional mutation in MSH2, MLH1 or Msh6 genes. We report one of the first moroccan case with Lynch syndrome whose constitutional mutation in the MLH1 gene was identified in a family member with colon cancer. In reply to the inquiry ofother healthy family members, a presymptomatic diagnosis was made allowing to formulate an appropriate monitoring strategy. Our study aims to highlight the role of oncogenetics in the management of patients with cancer and their families.

A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness.

OBJECTIVE: The m.3243A>G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare. RESEARCH DESIGN AND METHODS: We studied a patient presenting with diabetes and deafness who does not carry the m.3243A>G mutation. RESULTS: We identified a deficiency of respiratory chain complex I in the patient's fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient's somatic tissues. CONCLUSIONS: We describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mutation is likely favored by the m.14530T>C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability.

Haplotype frequencies for 17 Y-STR loci (AmpFlSTRY-filer) in a Moroccan population sample.

A sample of 267 unrelated Moroccan males from different ethnic groups (Arabs, Berbers and Sahrawi), was typed for 17 Y-STR loci (DYS19, DYS385, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, Y GATA H4). Discrimination capacity (96.3%) and haplotype diversity (99.91%) were calculated. A total of 257 haplotypes were identified, of which 237 were unique and 10 were found in two individuals each. DYS385 showed the highest diversity (0.887) followed by DYS458 (0.820) as a single locus marker.