الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Congenital muscular dystrophies (CMDs) are a group of inherited muscle disorders that are present at birth or in early infancy. They are characterized by weakness, delayed motor development, contractures, elevated CK, and abnormal muscle tissue on biopsy. CMDs are relatively rare, with an estimated prevalence of 0.5 to 0.9 per 100,000. However, the prevalence of CMDs is not well-known in developing countries. CMDs are caused by variants in genes that are important for muscle development and function. There are over 35 known CMDs genes, that can be divided into three broad categories: merosinopathies, dystroglycanopathies, and collagenopathies. Recently, CMDs are classified based on the affected proteins into variants in genes responsible of the basement membrane or extracellular matrix; variants in genes encoding endoplasmic reticulum proteins, variants in genes encoding intracellular and nuclear proteins, and variants in genes implicated in the glycosylation pathway.
The management of CMDs is mainly supportive, as there is still no definitive treatment available for any of the subtypes. The goal of management is to improve the quality of life and prevent complications.
The study aimed to identify different genetic variants that cause CMDs in a cohort of 20 Egyptian patients with suspected CMDs. This increases the effectiveness of genetic testing through understanding the molecular basis of CMDs in Egypt and thus providing better management and appropriate genetic counseling for the families.
After ethical approval from Alexandria University Egypt, and Rutgers University, USA, all the patients were subjected to:
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Detailed personal, pregnancy, and delivery history.
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Family history of similar condition or any other genetic disorders with 3-generation pedigree construction.
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Physical examination that focused on the differential diagnosis of CMDs subtypes.
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Anthropometric measurements included height, weight, and head circumference.
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CK level
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EMG
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MRI of the brain for different brain malformations.
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Ophthalmological assessment
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Molecular study included DNA extraction followed by Trio WES which is a next-generation sequencing method that involves library preparation, sequencing, and detection of variants in all exons of protein-coding genes in the genome. This in addition to splicing and CNV analysis. Finally, sanger confirmation of some identified variants.
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Bioinformatics pipeline included the following:
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Quality control
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Sequence alignment
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Variant calling
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Variant annotation
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Variant filtering
The study included 20 Egyptian patients with suspected congenital muscular dystrophy:
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Twelve male patients (60%) and eight female patients (40%) participated in the study.
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Sixteen patients were born to consanguineous parents (80%)
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Nine patients (45%) reported a family history of similar or related conditions.
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All patients presented with hypotonia along with delayed motor milestones.
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Intellectual disability was present in 45%.
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Brain MRI revealed abnormalities in 95% while eye abnormalities were detected in 45%.
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CK level was elevated 76% of patients.
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Seizures were reported in 40% while contractures were present in 30% of the cases.
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The WES results of the 17 studied patients, their parents, and affected sibs if present revealed a definitive molecular diagnosis in twelve patients (71%) while five patients (29%) remained unsolved with inconclusive variants in four of them.
Among the 12 solved patients, 11 patients (65%) had variants in known CMDs genes:
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Four variants in LAMA2 gene (23%)
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Two variants in both POMK and FKRP genes (12%),
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One variant in each of the POMT1, B3GALNT2, and COL6A1 genes (6%).
These variants were all rare and predicted to be pathogenic and six of them were novel and had not been previously reported in the literature.
The diagnosis for the remaining patient was the recently identified FLVCR1 severe spectrum which is considered as a differential diagnosis for WWS.
With regard to the five unsolved cases, the analysis of WES results found candidate variants in the NEURL1, RWDD2B, SOGA1, MTMR14, and SIGLEC16 genes. All of them were predicted to be pathogenic variants in genes that weren’t known to be disease-causing genes.