A recent study highlights 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. Researchers sought 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). They 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. Of note, there was a seemingly implausible transmission pattern in this family due to a mutation-negative obligate mutation carrier. They found:

• 4 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).
• 2 individuals were reported to be free of any disease.