A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Ngo, Kathie J.; Rexach, Jessica E.; Lee, Hane; Petty, Lauren E.; Perlman, Susan; Valera, Juliana M.; Deignan, Joshua L.; Mao, Yuanming; Aker, Mamdouh; Posey, Jennifer E.; Jhangiani, Shalini N.; Coban‐Akdemir, Zeynep; Boerwinkle, Eric; Muzny, Donna M.; Nelson, Alexandra; Hassin‐Baer, Sharon; Poke, Gemma; Neas, Katherine; Geschwind, Michael D.; Grody, Wayne W.; Gibbs, Richard A.; Geschwind, Daniel H.; Lupski, James R.; Below, Jennifer E.; Nelson, Stanley F.; Fogel, Brent L.

doi:10.1002/humu.23946

Cited by 63 publications

(57 citation statements)

References 83 publications

(201 reference statements)

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“…In total, we completed the exome analysis of 27 individuals and identified the genetic cause of their condition in 14 for a diagnosis rate of approximately 50%, similar to reported rates in well-resourced countries (Helbig et al, 2016;Ngo et al, 2020;Sawyer et al, 2016;Wright, FitzPatrick, & Firth, 2018). Currently, we have 11 additional exomes that await sequencing (Table 2).…”

Section: Laboratory Testingmentioning

confidence: 96%

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community

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Beighley

et al. 2020

American J of Med Genetics Pt C

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We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource‐limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2–3 clinics per year on various islands in the Caribbean. We also organized a week‐long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow‐up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

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Section: Laboratory Testingmentioning

confidence: 96%

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community

Sobering

Beighley

et al. 2020

American J of Med Genetics Pt C

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“…Roughly 50% of patients remain undiagnosed despite advanced genomic testing. [1][2][3][4] The most common genetic ataxias, as well as several rarer forms, are caused by nucleotide repeat expansions, which typically require targeted non-sequencebased testing to identify. [5][6][7][8] Recent studies identified a recessive intronic (AAGGG) repeat expansion in replication factor C subunit 1 (RFC1) related to cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) in Australia and the United Kingdom.…”

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confidence: 99%

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

et al. 2020

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ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.

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“…This variation was not detected in dbSNP146 [ 5 ], 1000 genome project [ 6 ], HGVD [ 7 ], or iJGVD [ 8 ], and the CADD score was 26.8 (deleterious > 20). Moreover, this variation was previously reported as a disease-causing variant in SPG9A [ 1 , 11 – 13 ]. These results showed Patients III-2 and III-3 had CMT1A, and Patients III-5, III-8, IV-1, IV-2, and IV-3 had SPG9A.…”

Section: Resultsmentioning

confidence: 88%

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

et al. 2021

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Background ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A. Case presentation A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine. Conclusions Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.

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A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Cited by 63 publications

References 83 publications

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community

Prevalence of RFC1 -mediated spinocerebellar ataxia in a North American ataxia cohort

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

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