Early diagnosis of Ullrich congenital muscular dystrophy associated with a novel COL6A1 variant: a case report

Abstract

Case Presentation: A two-year-old boy, born to non-consanguineous parents, was referred to medical genetics due to neurodevelopmental delay, peripheral hypotonia, congenital macrocephaly, and persistent mild hyperammonemia. His medical history included an incarcerated inguinal hernia and right cryptorchidism, both surgically corrected. At eight months of age, he was diagnosed with developmental dysplasia of the hip. Developmental milestones were delayed, with head control at four months, independent sitting at six months, and independent walking at two years of age. Language development was progressing, although phonological substitutions were noted. Social interaction was appropriate, although sensory sensitivities and selective eating were reported. Physical examination revealed hypotonia, hyporeflexia, knee contractures, distal joint hyperlaxity, broad forehead, oblique palpebral fissures, low nasal bridge, limb asymmetry, and eversion of the left foot with overlapping toes and clinodactyly. Creatine phosphokinase (CPK) levels were within normal limits. The patient showed poor weight gain (Z-score:-1). Initial investigation with chromosomal microarray yielded negative results. Whole-exome sequencing identified heterozygous pathogenic variants, presumed to be in trans (p.Met1?/c.739-2A>G), in the COL6A1 gene, confirming the molecular diagnosis of Ullrich congenital muscular dystrophy (UCMD). Discussion: UCMD belongs to the spectrum of collagen VI-related myopathies and results from pathogenic variants in COL6A1, leading to disruption of the muscle extracellular matrix. It is characterized by early hypotonia, motor delay, distal joint hypermobility associated with proximal contractures, and orthopedic abnormalities, with marked clinical heterogeneity. In this case, the combination of peripheral hypotonia, neurodevelopmental delay, and a characteristic joint pattern guided the early diagnostic investigation toward congenital myopathies. Whole-exome sequencing identified two heterozygous pathogenic variants in COL6A1, consistent with the autosomal recessive form; however, the allelic phase could not be determined. Final Comments: This report highlights the importance of early recognition of clinical features suggestive of UCMD combined with molecular investigation, enabling diagnostic confirmation in early childhood. Early diagnosis allows targeted clinical follow-up and multidisciplinary management, including motor and respiratory surveillance, as well as genetic counseling. The identification of a novel COL6A1 variant (c.1A>T) expands the mutational spectrum of UCMD and contributes to genotype-phenotype correlations in collagen VI-related disorders.