Abstract
Purpose: To alert the medical community that whole exome sequencing can find accessory gene changes in well-known syndromes that alter preventive health care and management. Meaning: A collagen type VI gene change adds muscle weakness, hypermobility, and dysautonomia concerns to usual management considerations for Down syndrome. Methods: Commercial whole exome sequencing combined with clinical interpretation of DNA sequence change added new considerations to patient management and parental counsel. Results: An 11-year-old child with the trisomy 21 form of Down syndrome who was evaluated for extraordinary joint laxity had a heterozygous collagen type VI aspartic to glutamic acid (COL6A3 c.6360 C>G p.Asp2120Glu) gene change found by whole exome sequencing. The DNA variant was qualified as having strong relevance to the enhanced hypermobility due to prior association of collagen 6 gene changes with myopathy. Conclusions: Dual diagnosis of Ehlers-Danlos syndrome was not assigned because the patient lacked criteria like bruising, unusual scars, or selected dysautonomia symptoms. The concept of a hypermobility spectrum offers advantages for management of its constituent conditions if clinically guided ascertainment and DNA diagnostics are employed.
Highlights
The approach from general to particular, so essential for Linnaean taxonomy and medical diagnosis, has been applied to hypermobility as the avatar of diseases like Ehlers-Danlos syndrome (EDS, [1] [2])
An 11-year-old child with the trisomy 21 form of Down syndrome who was evaluated for extraordinary joint laxity had a heterozygous collagen type VI aspartic to glutamic acid
Unusual flexibility or hypermobility occurs in two major disease categories, one involving low muscle tone with less constraint of joints, the other involving laxity of the joint tissue itself
Summary
The approach from general to particular, so essential for Linnaean taxonomy and medical diagnosis, has been applied to hypermobility as the avatar of diseases like Ehlers-Danlos syndrome (EDS, [1] [2]). Clinical recognition of hypermobility offers many benefits for patients, ranging from anticipatory guidance of joint injury and autonomic imbalance in its more benign forms [6] [7] to prevention of lethal cardiovascular complications in its extremes [8]. Another key to the recognition and differential diagnosis of hypermobility is appreciation of the many genes that must contribute to the synthesis and modulation of connective tissue [9], the medium that first enabled protists to become multicellular, the conveyer of messages that integrate cellular functions. DNA analysis can refine the diagnosis and management of hypermobility as shown by the following patient presentation and discussion
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