Importance: Chromosomal rearrangements are increasingly recognized to underlie neurologic disorders and are often accompanied by additional clinical signs beyond the gene-specific phenotypic spectrum.
Objective: To elucidate the causal genetic variant in a large US family with co-occurrence of dopa-responsive dystonia as well as skeletal and eye abnormalities (ie, ptosis, myopia, and retina detachment).
Design, setting, and participants: We examined 10 members of a family, including 5 patients with dopa-responsive dystonia and skeletal and/or eye abnormalities, from a US tertiary referral center for neurological diseases using multiple conventional molecular methods, including fluorescence in situ hybridization and array comparative genomic hybridization as well as large-insert whole-genome sequencing to survey multiple classes of genomic variations. Of note, there was a seemingly implausible transmission pattern in this family due to a mutation-negative obligate mutation carrier.
Main outcomes and measures: Genetic diagnosis in affected family members and insight into the formation of large deletions.
Results: Four members were diagnosed with definite and 1 with probable dopa-responsive dystonia. All 5 affected individuals carried a large heterozygous deletion encompassing all 6 exons of GCH1. Additionally, all mutation carriers had congenital ptosis requiring surgery, 4 had myopia, 2 had retinal detachment, and 2 showed skeletal abnormalities of the hands, ie, polydactyly or syndactyly or missing a hand digit. Two individuals were reported to be free of any disease. Analyses revealed complex chromosomal rearrangements on chromosome 14q21-22 in unaffected individuals that triggered the expansion to a larger deletion segregating with affection status. The expansion occurred recurrently, explaining the seemingly non-mendelian inheritance pattern. These rearrangements included a deletion of GCH1, which likely contributes to the dopa-responsive dystonia, as well as a deletion of BMP4 as a potential cause of digital and eye abnormalities.
Conclusions and relevance: Our findings alert neurologists to the importance of clinical red flags, ie, unexpected co-occurrence of clinical features that may point to the presence of chromosomal rearrangements as the primary disease cause. The clinical management and diagnostics of such patients requires an interdisciplinary approach in modern clinical-diagnostic care.