Different approach to genetic detection

Posted - June 2019 in Research Highlights

Success in 40% of cases

 

. . .

Treating a spectrum of overlapping conditions involving spasticity or ataxia as a single continuous group, whole genome sequencing detected genetic causes in 7/18 people for whom common causes of their conditions had previously been excluded.

 

Abstract

Inherited disorders of spasticity or ataxia exist on a spectrum with overlapping causative genes and phenotypes. We investigated the use of whole-genome sequencing (WGS) to detect a genetic cause when considering this spectrum of disorders as a single group.

We recruited 18 Korean individuals with spastic paraplegia with or without cerebellar ataxia in whom common causes of hereditary cerebellar ataxia and hereditary spastic paraplegia had been excluded. We performed WGS with analysis for single nucleotide variants, small insertions and deletions, copy number variants (CNVs), structural variants (SVs) and intronic variants.

Disease-relevant variants were identified in ABCD1 (n = 3), CAPN1 (n = 2), NIPA1 (n = 1) and PLA2G6 (n = 1) for 7/18 patients (38.9%). A ‘reverse phenotyping’ approach was used to clarify the diagnosis in individuals with PLA2G6 and ABCD1 variants. One of the ABCD1 disease-relevant variants was detected on analysis for intronic variants. No CNV or SV causes were found. The two males with ABCD1 variants were initiated on monitoring for adrenal dysfunction.

This is one of only a few studies to analyse spastic-ataxias as a continuous spectrum using a single approach. The outcome was improved diagnosis of unresolved cases for which common genetic causes had been excluded. This includes the detection of ABCD1 variants, which have management implications. Therefore, WGS may be particularly relevant to diagnosing spastic ataxias given the large number of genes associated with this condition and the relatively high diagnostic yield.

 

SOURCE: Cerebellum. 2019 May 18. doi: 10.1007/s12311-019-01038-0. [Epub ahead of print] PMID: 31104286

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing.

Kim A1, Kumar KR2,3,4,5, Davis RL6,7, Mallawaarachchi AC8, Gayevskiy V6, Minoche AE6, Walls Z6,9, Kim HJ10, Jang M11, Cowley MJ6,12,13, Choi JH10, Shin C14, Sue CM7,15, Jeon B10.

1 Department of Neurology, Chungbuk National University Hospital, Cheongju-si, South Korea.

2 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. [email protected]

3 Department of Neurogenetics, Kolling Institute, University of Sydney Faculty of Medicine and Health Northern Clinical School and Royal North Shore Hospital, St Leonards, NSW, Australia. [email protected]

4 Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia. [email protected]

5 Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia. [email protected]

6 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

7 Department of Neurogenetics, Kolling Institute, University of Sydney Faculty of Medicine and Health Northern Clinical School and Royal North Shore Hospital, St Leonards, NSW, Australia.

8 Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, NSW, Australia.

9 Faculty of Engineering & Information Technologies, The University of Sydney, Sydney, NSW, Australia.

10 Department of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

11 Department of Neurology, Presbyterian Medical Center, Jeonju, South Korea.

12 St Vincent’s Clinical School, UNSW Sydney, Sydney, NSW, Australia.

13 Children’s Cancer Institute, UNSW Sydney, Sydney, NSW, Australia.

14 Department of Neurology, Kyung Hee University Medical Center, Seoul, South Korea.

15 Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia.

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