Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited... Show moreRare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.CASE VIGNETTEIn 2017, Ipek (her name is used with permission), an apparently healthy baby girl, was born, but newborn screening (NBS) returned a result of concern: a low T-cell Receptor Excision Circle (TREC) count, raising the possibility immunodeficiency. Her ensuing medical evaluation disclosed no signs of severe combined immune deficiency, the usual target of this screening, but unexpectedly pointed to a different diagnosis: ataxia telangiectasia (A-T), a rare and progressive neurodegenerative disorder. In A-T, pathogenic variants in the ATM gene impair the cell's ability to respond to DNA damage, causing the cerebellum to begin to shrink starting in early childhood. The usual course of the disease includes development of symptoms by age five with development of clumsiness and incoordination. By their teenage years, the abilities to walk, talk, swallow, and coordinate her eye movements are lost. She would likely die as a young adult.No treatments for A-T exist. One of the challenges is that most children are diagnosed only after neurologic symptoms emerge, after significant degeneration has already occurred. But because Ipek was diagnosed at such a young age, she could be enrolled in an investigational trial before major neuronal loss. At age two, Ipek began receiving a series of intrathecal injections of an antisense oligonucleotide, designed by Boston Children's Hospital to suppress the effects of an abnormal splice site created by one of her pathogenic ATM variants (Yu lab, manuscript in review). This therapy promises her an improved long-term outcome that would otherwise have been impossible.In an age burgeoning with promising research studies for rare genetic diseases, this case underscores the importance of early screening for access to investigational trials. Early screening with whole-genome sequencing (WGS) can unlock opportunities for genetically targeted or other experimental therapies, such as the mutation-specific therapy designed for Ipek. For instance, 10%-15% of individuals with A-T have been shown to have splice mutations that could make them eligible for treatment with a splice-modulating ASO (and two-thirds of these cases are only detectable via WGS because they involve deep intronic variants and/or structural genomic rearrangements). In the future, early WGS may unlock opportunities for additional targeted therapies like nonsense readthrough or RNA or genome editing. Show less
Cappuccio, G.; Brillante, S.; Tammaro, R.; Pinelli, M.; Bernardi, M.L. de; Gensini, M.G.; ... ; Brunetti-Pierri, N. 2022
Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Stromme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly.... Show moreBiallelic loss-of-function (LoF) variants in CENPF gene are responsible for Stromme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Stromme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Stromme syndrome. Show less
Ostrowski, P.J.; Zachariou, A.; Loveday, C.; Beleza-Meireles, A.; Bertoli, M.; Dean, J.; ... ; Tatton-Brown, K. 2019
CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated... Show moreCHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference >= 2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (<= 15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability. Show less
