Complex and Dynamic Chromosomal Rearrangements in a Family With Seemingly Non-Mendelian Inheritance of Dopa-Responsive Dystonia

Abstract

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.

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

“…Whole-genome sequencing (WGS) studies have shown that cxSVs are considerably more abundant and diverse than had been previously appreciated, representing an estimated 2% of the SVs in the human genome, and each human genome contains on average 14 cxSVs [ 11 ]. The presence of multiple types of cxSVs has also been independently observed in several other studies [ 5 , 12 – 14 ]. Extreme cases of cxSVs, such as chromothripsis, have also been identified in both cancer cells and the germline and involve hundreds of rearrangements often concerning more than one chromosome [ 11 , 15 ].…”

Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

“…The rearrangements can include deletions, insertions, and inversions of one or more trangene sequences . A similar chromothripsis of human genomes occurs in autism and related neurodevelopmental disorders, suggesting that structural alterations in the genome can alter neuronal function Lohmann et al, 2017;Talkowski et al, 2012). We wondered whether a similar complex genetic rearrangement occurred in Nd1 and Nd2 transgenes leading to a toxic gain-of-function.…”

Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases

“…In addition, several individuals were reported to have delayed motor milestones. Interestingly, subjects 2 and 3 both had deletions involving the GCH1 gene, which was recently implicated in disease in a family with autosomal dominant or recessive doparesponsive dystonia in addition to eye and skeletal anomalies attributed to BMP4 haploinsufficiency [15]. However, dystonia was not reported in either of the newly reported cases described in this study.…”

“…Overall, only a few studies have been published examining the phenotypic spectrum associated with BMP4 deletions and loss-of-function variants. Recently, a large family with dopa-responsive dystonia, eye, and skeletal anomalies was reported with a complex chromosomal rearrangement involving at 14q21q22, which resulted in the deletion of BMP4 and GTP cyclohydrolase 1 (GCH1, MIM# 600225); deletion of these genes could independently explain the complex phenotype and inheritance pattern observed in this family [15]. Several new studies have also emphasized the importance of considering multiple, independent molecular diagnoses in subjects with atypical or 'expanded' phenotypes [16].…”