Evidence map›Paper›PMID 41349538›Full record

ArticleAmerican journal of human genetics2026

Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.

James Fasham, Julia Rankin, Rachel Schot, Susan M White, Katrina M Bell, Matthew N Wakeling, Lucy J Mallin, Alex Shah, Michelle G de Silva, David I Francis and 33 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

43 authors.

James FashamDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK; Department of Clinical Genetics, Royal Devon University Hospital, EX1 2ED Exeter, UK.
Julia RankinDepartment of Clinical Genetics, Royal Devon University Hospital, EX1 2ED Exeter, UK.
Rachel SchotDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Susan M WhiteVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
Katrina M BellVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Matthew N WakelingDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Lucy J MallinExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, EX2 5DW Exeter, UK.
Alex ShahUniversity Hospitals Plymouth NHS Trust, Derriford Road, Crownhill, Plymouth, PL6 8DH Devon, UK.
Michelle G de SilvaVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
David I FrancisVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
Maie WalshGenomic Medicine, the Royal Melbourne Hospital, Parkville, VIC, Australia.
Emily E JonesBristol Genetics Laboratory, North Bristol NHS Trust, BS10 5NB Bristol, UK.
Kayal VijayakumarDepartment of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, BS1 3NU Bristol, UK.
Katie JohnsonNottingham Regional Genetics Service, Nottingham City Hospital Campus, The Gables, NG5 1PB Nottingham, UK.
Francis H SansburyAll Wales Medical Genomics Service, NHS Wales Cardiff and Vale University Health Board, Wales Genomic Health Centre, Cardiff Edge Business Park, Longwood Drive, Whitchurch, CF14 7YU Cardiff, UK; Division of Cancer & Genetics, School of Medicine, Cardiff University, CF14 4XN Cardiff, UK.
Johann Te Water NaudéDepartment of Paediatric Neurology, University Hospital of Wales, CF14 4XW Cardiff, UK.
Paola GiuntiQueen Square Institute of Neurology, WC1N 3BG London, UK.
Marios HadjivassiliouAcademic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and University of Sheffield, S10 2JF Sheffield, UK.
Andrea H NemethNuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU Oxford, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, OX3 7LD Oxford, UK.
George K TofarisNuffield Department of Clinical Neurosciences, University of Oxford, OX3 9DU Oxford, UK; Department of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, OX3 9DU Oxford, UK.
Carlo RinaldiDepartment of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, OX3 9DU Oxford, UK; Institute of Developmental and Regenerative Medicine, University of Oxford, OX3 7TY Oxford, UK.
Benito Banos-PineroOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, OX3 9DU Oxford, UK.
Marianna SelikhvaNeurology Department, Southmead Hospital, BS10 5NB Bristol, UK.
Nishanka UbeyratnaDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Anneke KievitDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Frank SleutelsDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Joey van GiessenDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Timothy S HallDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Alan WhoneSouthmead Hospital, BS10 5NB Bristol, UK.
Eleanor ThomasDepartment of Child Health, Royal Devon University Hospital, EX1 2ED Exeter, UK.
Joseph S LeslieDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Rosemary A BamfordDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Aaron R JeffriesBiosciences, University of Exeter, EX1 2LU Exeter, UK.
Jenny LordSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, S10 2HQ Sheffield, UK.
Susan WalkerGenomics England, EC1M 6BQ London, UK.
Tjakko J van HamDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Sue L HillNHS England, London, UK.
Lucy McGavinUniversity Hospitals Plymouth NHS Trust, Derriford Road, Crownhill, Plymouth, PL6 8DH Devon, UK; University of Plymouth, PL4 8AA Plymouth, UK.
Andrew ParrishExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, EX2 5DW Exeter, UK.
Andrew H CrosbyDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK.
Emma L BapleDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK; Department of Clinical Genetics, Royal Devon University Hospital, EX1 2ED Exeter, UK. Electronic address: e.baple@exeter.ac.uk.
Alistair T PagnamentaDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, EX2 5DW Exeter, UK. Electronic address: a.pagnamenta@exeter.ac.uk.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H

Indexed as

AtaxiaChromosomes, Human, Pair 16Neurodegenerative DiseasesAdolescentAdultChildDNA Copy Number VariationsFemaleHumansMalePedigreePhenotypeVacuolar Proton-Translocating ATPasesYoung AdultVacuolar Proton-Translocating ATPasesataxiaATP6V0Ccerebellar hypoplasiaCNVduplication-triplicationgene dosageinversionstructural variant

Identifiers

PMID41349538
PMCPMC12824621

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