Hypotonic syndrome as a manifestation of an ultra-rare disease caused by a new and de novo variant in the PLA2G6 gene

Introduction: congenital hypotonia, a rare condition that encompasses various neuromuscular disorders, can have a genetic origin, such as infantile neuroaxonal dystrophy (inad), an ultra-rare neurodegenerative disorder of unknown prevalence. Objective: to utilize genomic techniques for the precision diagnosis of low-prevalence neuromuscular diseases. Materials and methods: case report of an infant, without a family history of genetic diseases, normal pregnancy, hypotonia at birth, neurodevelopmental regression, nystagmus, strabismus, and cerebellar atrophy. Due to the suspicion of an autosomal recessive vs de novo inherited disease, genetic sequencing studies using ngs (next-generation sequencing) + cnv (copy number variations) were requested for genes related to congenital hypotonia (1,621 genes). Results: two heterozygous variants were identified (compound heterozygote for the pla2g6 gene), the first variant classified as probably pathogenic, a duplication of 5 nucleobases at position 1,914 of the cdna, in exon 14 of the gene. The second variant, classified as pathogenic, involves a change from guanine to adenine at position 2,081 of the cdna, in exon 15 of the gene. Variants in this gene are associated with three autosomal recessive medical conditions: infantile neuroaxonal dystrophy 1, neurodegeneration with brain iron accumulation 2b, and parkinsons disease 14. Discussion and conclusion: congenital hypotonia, linked to disorders such as inad, is difficult to diagnose conventionally. Deleterious variants in the pla2g6 gene, located on chromosome 22, are associated with three autosomal recessive hereditary conditions, including inad, with manifestations before 3 years of age, neurological symptoms, mortality within the first decade, and multiple complications. Genomic technologies, including reverse phenotyping, are fundamental in understanding its genetic basis, phenotypic heterogeneity, guiding targeted treatment, prognosis, follow-up, genetic counseling, and heritability risk, bringing us closer to anticipatory, preventive, and precision medicine, especially in ultra-rare conditions.