A series of four patients with Sotos syndrome harboring novel NSD1 mutations: clinical and molecular description.

BACKGROUND: Sotos syndrome is a rare and complex genetic disorder caused by haploinsufficiency of the NSD1 gene. This syndrome is characterized by rapid early childhood growth, distinct facial features, a learning disability, and multiple other developmental and behavioral challenges. METHODS AND RESULTS: In this work, we describe four Moroccan patients with variable clinical presentations of Sotos syndrome, in whom we identified four novel NSD1 monoallelic pathogenic variants by conducting targeted Next Generation Sequencing. Genetic testing allowed us to provide a precise medical diagnosis to our patients and tailor interventions to each patient's needs. CONCLUSIONS: Being the first work describing a series of Moroccan patients with this syndrome, this case series contributes to the growing body of literature on Sotos syndrome and provides valuable insights into the clinical and molecular characteristics of this rare disorder.

Mutational spectrum of BRCA1/2 genes in Moroccan patients with hereditary breast and/or ovarian cancer, and review of BRCA mutations in the MENA region.

PURPOSE: Breast cancer (BC) is the most common form of female cancer around the world. BC is mostly sporadic, and rarely hereditary. These hereditary forms are mostly BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome. BRCA1 and BRCA2 genes are large and had some recurrent mutations specific to some populations. Through this work we analyze the most recurrent mutations in Moroccan population and compared them to a large review of other BRCA1/2 spectrum mutations in the MENA region. METHODS: We report in this work a series of 163 unrelated patients (the largest series of Moroccan patients) with familial breast and/or ovarian cancer, selected among patients referred to our oncogenetic outpatient clinic, from 2006 to 2021. To identify genetic variants in these two genes, different genetic analysis strategies have been carried out, using Sanger Sequencing DNA or Target Panel Sequencing. RESULTS: Pathogenic variants were identified in 27.6% of patients. The most frequent mutation identified in our patients was the c.1310_1313delAAGA, BRCA2 (33%), and three other mutations seem more frequent in the Moroccan population (33%) of all reported patients: c.798_799delTT, BRCA1; and c.3279delC, BRCA1; and c.7234_7235insG in BRCA2 gene. CONCLUSION: Through this work, we emphasize the importance of screening for BRCA1 and BRCA2 recurrent mutations in Moroccan patients. Other MENA (MENA: English-language acronym referring to the Middle East and North Africa region) countries had also some recurrent BRCA mutations, which will allow a fast and unexpensive first line genetic analysis and a precise molecular diagnosis. This will allow an adapted follow-up of the patients and a pre-symptomatic diagnosis of their relatives.

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.

Further evidence of POP1 mutations as the cause of anauxetic dysplasia.

Anauxetic dysplasia (AAD, OMIM 607095) is a rare skeletal dysplasia inherited as an autosomal recessive trait, which is caused by mutations in RMRP and allelic to a more common disorder, cartilage hair hypoplasia (CHH). CHH is a multi-system disorder with a variety of extraskeletal changes. Whereas AAD is a bone-restricted disorder with a more severe skeletal phenotype: affected individuals are extremely short and complicated by orthopedic morbidity, and the radiological changes include modification of the vertebral bodies and epiphyseal dysplasia of the hip, as well as generalized metaphyseal dysplasia and severe brachydactyly. Recently, genetic heterogeneity for AAD was proposed, because a familial case (two affected sibs) with an AAD-identical phenotype had compound heterozygous mutations in POP1, encoding a molecule functionally related to the gene product of RMRP. We report here a 5-year-old boy with the same phenotype born to a consanguineous couple. We identified a novel homozygous POP1 mutation (c.1744C>T, p.P582S) in the boy and the heterozygosity in the parents. It may be rational to coin the POP1-associated skeletal phenotype AAD type 2. © 2016 Wiley Periodicals, Inc.

Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type.

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-abnormal calcification type (SMED, SL-AC), is a very rare autosomal recessive disorder with various skeletal changes characterized by premature calcification leading to severe disproportionate short stature. Twenty-two patients have been reported until now, but only five mutations (four missense and one splice-site) in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene has been identified. We report here a novel DDR2 missense mutation, c.370C > T (p.Arg124Trp) in a Moroccan girl with SMED, SL-AC, identified by whole exome sequencing. Our study has expanded the mutational spectrum of this rare disease and it has shown that exome sequencing is a powerful and cost-effective tool for the diagnosis of clinically heterogeneous disorders such as SMED.

Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population.

BACKGROUND: Several pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual's acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH. Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins. The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity. RESULTS: The frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group. CONCLUSION: The most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators. This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects.

Characterization of a rare short arm heteromorphism of chromosome 22 in a girl with down-syndrome like facies.

Chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence. Chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1, 9, 16 and Y and the short arms of all acrocentric chromosomes. Here, we report a girl with Down-syndrome such as facies and tremendously enlarged short arm of a chromosome 22. Fluorescence in situ hybridization (FISH) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm. Parental studies identified a maternal origin of this heteromorphism. Cryptic trisomy 21 of the Down-syndrome critical region was excluded by a corresponding FISH-probe. Here, we report, to the best of our knowledge, largest ever seen chromosome 22 short arm, being ~×1.5 larger than the normal long arm.

Novel Splice Site Pathogenic Variant in STXBP1 Gene in a Child with Intellectual Disability, Epilepsy, and Autism Spectrum Disorder: A Case Report.

Introduction: Pathogenic variants in the STXBP1 gene are associated to a large spectrum of severe early onset developmental and epileptic encephalopathies (OMIM #612164). They were also identified in various other neurodevelopmental disorders. This gene encodes for the syntaxin-binding protein 1, a member of the SEC-1 family of membrane-transport proteins that modulate the presynaptic vesicular fusion by interacting with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). However, the physiopathology of STXBP1 pathogenic variants is not yet fully understood. Case Presentation: Herein, we report a patient presenting intellectual disability, early onset seizures, and autism. Clinical exome sequencing identified a novel monoallelic splice pathogenic variant STXBP1(NM_001032221.6):c.38-2A>G. Discussion: Splice-site pathogenic variants in the STXBP1 gene are mostly associated with West syndrome, early onset epilepsy and encephalopathy, and Ohtahara syndrome. Our findings extend clinical and molecular spectrum of STXBP1 gene variants by reporting the first splice-site variant associated with autism along with early onset epilepsy and, and intellectual disability in a patient.

Novel variant related to SATB2-associated syndrome.

BACKGROUND: SATB2-associated syndrome (SAS) also known as Glass syndrome is characterized by/intellectual disability and/or developmental delay coupled with absent or limited speech development. Other abnormalities can be noticed including craniofacial anomalies such as palatal and dental anomalies, behavioural problems and dysmorphic features. It is associated with pathogenic monoallelic variants of the SATB2 gene known to play a key role in brain, dental and jaw development. As phenotype could be unspecific and progressive, clinical diagnostic is difficult. Therefore, genetic testing is mandatory to confirm the disease. Herein, we report clinical and molecular data of a 13-year-old girl with psychomotor developmental delay and behavioural problems. METHODS AND RESULTS: Next-generation sequencing detected the novel monoallelic frameshift variant SATB2(NM_001172509.2): c.1135del(p.Gln379Lysfs*34). Currently, this variant is classified as likely pathogenic according to the American College of Medical Genetics. Sanger sequencing was used to validate the presence of the detected variant in the patient and confirm de novo character of this latter. CONCLUSION: Through this work, we emphasize the value of next-generation sequencing for a precise molecular diagnosis, an adapted clinical management of patients and an adequate genetic counselling of their families.

An inherited LMNA gene mutation in atypical Progeria syndrome.

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.