Novel COL6A1 Gene Variant Linked to Rare Muscle Disorder in Child

A single genetic letter change in the COL6A1 gene may explain the severe muscle weakness of a three-year-old boy born to consanguineous parents, according to a case report published in Clinical Case Reports. The child, who presented with congenital hypotonia and global developmental delay, was found through whole exome sequencing to carry a novel homozygous missense variant, c.2821C>T, which substitutes phenylalanine for leucine at position 941 of the collagen alpha-1(VI) protein. The variant has been deposited in the ClinVar database under accession number SCV007518538, but because no functional or population data existed for it, it was formally classified as a Variant of Uncertain Significance, or VUS. The clinical picture, however, tells a more decisive story, and the case illustrates the ongoing tension between raw genomic data and bedside medicine in the diagnosis of rare neuromuscular disease.

Collagen type VI is a microfibrillar collagen found throughout the extracellular matrices of skeletal muscle and connective tissue. It anchors muscle fibers to their surrounding scaffold, maintains the structural integrity and elasticity of blood vessels, skin, and joints, and interacts with integrins while regulating various growth factors. Three genes, COL6A1, COL6A2, and COL6A3, encode the alpha chains that assemble into the functional collagen VI network. When pathogenic variants disrupt this assembly, the result is a continuum of neuromuscular disorders known as collagen VI-related dystrophies. At the mild end sits Bethlem myopathy, historically described as an autosomal dominant condition, while the severe end is occupied by Ullrich congenital muscular dystrophy, a devastating disease that can arise from either recessive or dominant mutations depending on the molecular mechanism involved.

Ullrich congenital muscular dystrophy was first described by Otto Ullrich in 1930 and is estimated to affect roughly 0.13 per 100,000 people worldwide. Its presentation is famously paradoxical: early-onset generalized hypotonia and severe proximal joint contractures coexist with marked hyperlaxity of the distal joints, a combination that gives affected children a distinctive posture and unusual joint mobility at the fingers, wrists, and ankles. Most patients experience significant motor delays, and disease progression inexorably leads to restrictive respiratory failure, which remains the primary cause of illness and death within the first two decades of life. There is currently no curative treatment. Management depends on a proactive multidisciplinary approach built around supportive care, early respiratory monitoring, and intensive physical therapy to slow contracture progression and preserve whatever motor function remains.

The boy in this report was born at term after an uncomplicated pregnancy and normal spontaneous vaginal delivery, with birth weight, length, and head circumference all within normal limits. His parents are first cousins, a detail that would prove central to the diagnostic story. Abnormal neuromuscular features emerged within the first month of life, when clinicians noted dysmorphic features including low-set ears, a high-arched palate, and a low anterior hairline, alongside clenched fingers more pronounced on the right side and a congenital clubfoot deformity. These findings prompted longitudinal developmental follow-up, which revealed a significant global delay. At age three, the child cannot sit independently, though he can sit with support, and he remains nonverbal. Receptive language appears spared, as he responds consistently to simple commands and to his name, and social development is largely maintained with appropriate eye contact and social smiling.

Neurological examination showed generalized hypotonia affecting both the trunk and the limbs, with distal muscle weakness more pronounced than proximal weakness. Deep tendon reflexes were globally absent, yet there were no signs of lower motor neuron disease such as tongue atrophy or fasciculation, and no seizures or hearing and vision problems were reported. Given the combination of developmental delay, hypotonia, progressive joint contractures, and the consanguineous parentage, clinicians pursued a genetic cause early and turned to whole exome sequencing. The test uncovered the homozygous COL6A1 variant of uncertain significance. Serum creatine phosphokinase, a muscle enzyme that rises sharply in many muscular dystrophies, was measured twice and found to be entirely normal at 78 and 114 units per liter against a reference range of 0 to 190.

To characterize the neuromuscular phenotype further, the team performed nerve conduction studies and electromyography. Nerve conduction studies revealed decreased compound motor action potential amplitudes in several motor nerves; the response of the left median motor nerve was absent altogether, while the right median nerve showed reduced amplitude with decreased conduction velocity, though interpretation was limited by the child’s hand deformities and joint contractures. Electromyography showed normal spontaneous activity but early recruitment of small motor units in the left tibialis anterior muscle, a pattern the neurophysiologists interpreted as non-specific myopathic change. Brain magnetic resonance imaging, obtained as part of the developmental delay workup, showed prominence of the anterior horns of the lateral ventricles, widening of the Sylvian fissures, and a diffuse reduction in white matter volume, all described as non-specific findings.

The diagnostic reasoning hinged on excluding alternatives. Spinal muscular atrophy, a leading cause of the floppy infant, was considered but deemed highly unlikely given the absence of tongue fasciculations, intact receptive language, and myopathic rather than neurogenic changes on electromyography. Other congenital myopathies and muscular dystrophies were also weighed, but the normal creatine phosphokinase levels effectively ruled out most dystrophinopathies and alpha-dystroglycanopathies, which typically produce markedly elevated enzyme values. The distinct structural abnormalities, clenched fingers and clubfoot, further aligned the phenotype specifically with collagen VI deficiency rather than other central or peripheral causes of hypotonia, and the paradoxical pairing of distal hypermobility with progressive proximal contractures pointed squarely toward the Ullrich end of the collagen VI disease spectrum.

Genetically, the variant itself fits the known disease mechanism even though it lacks formal classification. Pathogenic missense variants affecting highly conserved residues within the triple-helical domains of collagen are well-established causes of Ullrich congenital muscular dystrophy, and similar novel homozygous COL6A1 missense variants, such as p.Gly556Val, have previously been identified as the direct cause of classic disease features in consanguineous families. Splice-site and non-coding variants in COL6A1 have likewise been shown to disrupt collagen VI formation even when initially designated as uncertain. One atypical feature complicates the picture: the child’s significant global developmental delay, particularly in expressive language, is unusual for collagen VI-related dystrophies, in which cognitive function is classically spared. The exome did not reveal any secondary genetic variants to explain the delay, so the authors suggest it may relate to the diffuse white matter reduction seen on MRI, or may be secondary to severe early motor impairment and limited environmental interaction, though an independent co-occurring cause cannot be excluded.

The case also carries public health significance beyond a single patient. Epidemiological data on collagen VI-related dystrophies in the Middle East remain remarkably scarce, and Arab populations, including those in Palestine, have high rates of consanguineous marriage, which substantially increases the incidence of rare autosomal recessive conditions. In this child, the first-cousin parentage directly enabled the expression of a homozygous mutation that would likely remain silent in a heterozygous carrier. Documenting such cases, the authors argue, expands the global mutational spectrum of COL6A1 and underscores the need for targeted genetic counseling and carrier screening in highly consanguineous communities, where recessive diagnoses cluster within extended families.

The report acknowledges its limitations honestly. Segregation analysis was not performed because parental genetic testing was unavailable, and no functional studies, such as muscle biopsy, collagen VI immunohistochemistry on skin biopsy, or fibroblast culture, were carried out, all of which would be needed to upgrade the variant from uncertain to pathogenic under strict American College of Medical Genetics and Genomics criteria. Muscle MRI, which can reveal characteristic patterns of fibro-fatty replacement in collagen VI-related dystrophies, was also not performed, largely because of resource constraints and the clinical risks of prolonged general anesthesia or deep sedation in a child with severe hypotonia. Even so, the strong genotype-phenotype correlation documented here provides exactly the kind of phenotypic evidence that geneticists need to reclassify variants of uncertain significance in the future. For families navigating the uncertainty of an unclassified genetic result, careful clinical description remains one of the most powerful diagnostic tools available, turning a single ambiguous line of sequence data into a meaningful answer about a child’s disease.

Subject of Research: A novel COL6A1 gene variant associated with Ullrich congenital muscular dystrophy in a child with congenital hypotonia

Article Title: Unclassified COL6A1 Variant in a Child With Congenital Hypotonia: A Case Report

Article References: Nofal, K., Ghaith, H. M. A., Barghouthi, H. A., Shahrori, M., Darraj, B., & Hetta, A. A. (2026). Unclassified COL6A1 Variant in a Child With Congenital Hypotonia: A Case Report. Clinical Case Reports, 14(10), Article e73765. https://doi.org/10.1002/ccr3.73765

Image Credits: AI Generated

DOI: 10.1002/ccr3.73765

Keywords: COL6A1, Ullrich congenital muscular dystrophy, collagen VI-related dystrophies, congenital hypotonia, whole exome sequencing, variant of uncertain significance, consanguinity, neuromuscular disorders, genetic diagnosis, ClinVar, muscle weakness, rare disease