An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy

<div><p>The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved i...

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المؤلف الرئيسي:	Alistair T Pagnamenta (18595567) (author)
مؤلفون آخرون:	Rauan Kaiyrzhanov (11494177) (author), Yaqun Zou (4678174) (author), Sahar I Da'as (18595570) (author), Reza Maroofian (5237852) (author), Sandra Donkervoort (8411904) (author), Natalia Dominik (17724721) (author), Marlen Lauffer (18595573) (author), Matteo P Ferla (18595576) (author), Andrea Orioli (18595579) (author), Adam Giess (849800) (author), Arianna Tucci (13233424) (author), Christian Beetz (499802) (author), Maryam Sedghi (18595582) (author), Behnaz Ansari (18595585) (author), Rita Barresi (251871) (author), Keivan Basiri (18595588) (author), Andrea Cortese (4599292) (author), Greg Elgar (5184) (author), Miguel A Fernandez-Garcia (18595591) (author), Janice Yip (18595594) (author), A Reghan Foley (16163288) (author), Nicholas Gutowski (3469028) (author), Heinz Jungbluth (3569084) (author), Saskia Lassche (15274039) (author), Tim Lavin (18595597) (author), Carlo Marcelis (206539) (author), Peter Marks (3404351) (author), Chiara Marini-Bettolo (18595600) (author), Livija Medne (3401177) (author), Ali-Reza Moslemi (456876) (author), Anna Sarkozy (672243) (author), Mary M Reilly (9260636) (author), Francesco Muntoni (228210) (author), Francisca Millan (12157194) (author), Colleen C Muraresku (18595603) (author), Anna C Need (18595606) (author), Andrea H Nemeth (18595609) (author), Sarah B Neuhaus (18595612) (author), Fiona Norwood (3569075) (author), Marie O'Donnell (12599998) (author), Mary O’Driscoll (18595615) (author), Julia Rankin (7813010) (author), Sabrina W Yum (18595618) (author), Zarazuela Zolkipli-Cunningham (5234186) (author), Isabell Brusius (16838785) (author), Gilbert Wunderlich (17954830) (author), John C Ambrose (12453972) (author), Prabhu Arumugam (13567201) (author), Emma L Baple (15449710) (author), Marta Bleda (3508925) (author), Freya Boardman-Pretty (18595621) (author), Jeanne M Boissiere (18595624) (author), Christopher R Boustred (18595627) (author), Helen Brittain (18595630) (author), Mark J Caulfield (7948367) (author), Georgia C Chan (18595633) (author), Clare E H Craig (18595636) (author), Louise C Daugherty (18595639) (author), Anna de Burca (18595642) (author), Andrew Devereau (7595366) (author), Rebecca E Foulger (18595645) (author), Tom Fowler (3624713) (author), Pedro Furió-Tarí (3200460) (author), Joanne M Hackett (18595648) (author), Dina Halai (15102816) (author), Angela Hamblin (3746083) (author), Shirley Henderson (3119961) (author), James E Holman (18595651) (author), Tim J P Hubbard (16230509) (author), Kristina ibáñez (18595654) (author), Rob Jackson (9020126) (author), Louise J Jones (16220519) (author), Dalia Kasperaviciute (16277066) (author), Melis Kayikci (239001) (author), Athanasios Kousathanas (493642) (author), Lea Lahnstein (18595657) (author), Kay Lawson (18595660) (author), Sarah E A Leigh (18595663) (author), Ivonne U S Leong (18595666) (author), Javier F Lopez (18595669) (author), Fiona Maleady-Crowe (18595672) (author), Joanne Mason (3520556) (author), Ellen M McDonagh (18595675) (author), Loukas Moutsianas (282004) (author), Michael Mueller (669639) (author), Nirupa Murugaesu (594421) (author), Peter O’Donovan (8564949) (author), Chris A Odhams (18595681) (author), Christine Patch (10875074) (author), Mariana Buongermino Pereira (5126858) (author), Daniel Perez-Gil (6525827) (author), Dimitris Polychronopoulos (558617) (author), John Pullinger (13768447) (author), Tahrima Rahim (18595687) (author), Augusto Rendon (147779) (author), Pablo Riesgo-Ferreiro (10909735) (author), Tim Rogers (6685226) (author), Mina Ryten (347609) (author), Kevin Savage (5229500) (author), Kushmita Sawant (18595690) (author), Richard H Scott (13567189) (author), Afshan Siddiq (151264) (author), Alexander Sieghart (18595693) (author), Damian Smedley (2514) (author), Katherine R Smith (13595329) (author), Samuel C Smith (18595696) (author), Alona Sosinsky (762286) (author), William Spooner (14317) (author), Helen E Stevens (17207455) (author), Alexander Stuckey (4512469) (author), Razvan Sultana (1205) (author), Mélanie Tanguy (4691986) (author), Ellen R A Thomas (18595699) (author), Simon R Thompson (18595702) (author), Carolyn Tregidgo (18595705) (author), Emma Walsh (13558381) (author), Sarah A Watters (18595708) (author), Matthew J Welland (18595711) (author), Eleanor Williams (5144555) (author), Katarzyna Witkowska (8950625) (author), Suzanne M Wood (18595714) (author), Magdalena Zarowiecki (3242406) (author), Mert Karakaya (3574748) (author), Brunhilde Wirth (191925) (author), Khalid A Fakhro (18295393) (author), Homa Tajsharghi (456877) (author), Carsten G Bönnemann (18595717) (author), Jenny C Taylor (18595720) (author), Henry Houlden (110428) (author), Genomics England Research Consortium (7845782) (author)
منشور في:	2021
الموضوعات:	Biological sciences Genetics Biomedical and clinical sciences Neurosciences hereditary motor and sensory neuropathies nerve conduction studies EMG genetics neuropathy whole-genome sequencing
الوسوم:	إضافة وسم لا توجد وسوم, كن أول من يضع وسما على هذه التسجيلة!

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author	Alistair T Pagnamenta (18595567)
author2	Rauan Kaiyrzhanov (11494177) Yaqun Zou (4678174) Sahar I Da'as (18595570) Reza Maroofian (5237852) Sandra Donkervoort (8411904) Natalia Dominik (17724721) Marlen Lauffer (18595573) Matteo P Ferla (18595576) Andrea Orioli (18595579) Adam Giess (849800) Arianna Tucci (13233424) Christian Beetz (499802) Maryam Sedghi (18595582) Behnaz Ansari (18595585) Rita Barresi (251871) Keivan Basiri (18595588) Andrea Cortese (4599292) Greg Elgar (5184) Miguel A Fernandez-Garcia (18595591) Janice Yip (18595594) A Reghan Foley (16163288) Nicholas Gutowski (3469028) Heinz Jungbluth (3569084) Saskia Lassche (15274039) Tim Lavin (18595597) Carlo Marcelis (206539) Peter Marks (3404351) Chiara Marini-Bettolo (18595600) Livija Medne (3401177) Ali-Reza Moslemi (456876) Anna Sarkozy (672243) Mary M Reilly (9260636) Francesco Muntoni (228210) Francisca Millan (12157194) Colleen C Muraresku (18595603) Anna C Need (18595606) Andrea H Nemeth (18595609) Sarah B Neuhaus (18595612) Fiona Norwood (3569075) Marie O'Donnell (12599998) Mary O’Driscoll (18595615) Julia Rankin (7813010) Sabrina W Yum (18595618) Zarazuela Zolkipli-Cunningham (5234186) Isabell Brusius (16838785) Gilbert Wunderlich (17954830) John C Ambrose (12453972) Prabhu Arumugam (13567201) Emma L Baple (15449710) Marta Bleda (3508925) Freya Boardman-Pretty (18595621) Jeanne M Boissiere (18595624) Christopher R Boustred (18595627) Helen Brittain (18595630) Mark J Caulfield (7948367) Georgia C Chan (18595633) Clare E H Craig (18595636) Louise C Daugherty (18595639) Anna de Burca (18595642) Andrew Devereau (7595366) Rebecca E Foulger (18595645) Tom Fowler (3624713) Pedro Furió-Tarí (3200460) Joanne M Hackett (18595648) Dina Halai (15102816) Angela Hamblin (3746083) Shirley Henderson (3119961) James E Holman (18595651) Tim J P Hubbard (16230509) Kristina ibáñez (18595654) Rob Jackson (9020126) Louise J Jones (16220519) Dalia Kasperaviciute (16277066) Melis Kayikci (239001) Athanasios Kousathanas (493642) Lea Lahnstein (18595657) Kay Lawson (18595660) Sarah E A Leigh (18595663) Ivonne U S Leong (18595666) Javier F Lopez (18595669) Fiona Maleady-Crowe (18595672) Joanne Mason (3520556) Ellen M McDonagh (18595675) Loukas Moutsianas (282004) Michael Mueller (669639) Nirupa Murugaesu (594421) Peter O’Donovan (8564949) Chris A Odhams (18595681) Christine Patch (10875074) Mariana Buongermino Pereira (5126858) Daniel Perez-Gil (6525827) Dimitris Polychronopoulos (558617) John Pullinger (13768447) Tahrima Rahim (18595687) Augusto Rendon (147779) Pablo Riesgo-Ferreiro (10909735) Tim Rogers (6685226) Mina Ryten (347609) Kevin Savage (5229500) Kushmita Sawant (18595690) Richard H Scott (13567189) Afshan Siddiq (151264) Alexander Sieghart (18595693) Damian Smedley (2514) Katherine R Smith (13595329) Samuel C Smith (18595696) Alona Sosinsky (762286) William Spooner (14317) Helen E Stevens (17207455) Alexander Stuckey (4512469) Razvan Sultana (1205) Mélanie Tanguy (4691986) Ellen R A Thomas (18595699) Simon R Thompson (18595702) Carolyn Tregidgo (18595705) Emma Walsh (13558381) Sarah A Watters (18595708) Matthew J Welland (18595711) Eleanor Williams (5144555) Katarzyna Witkowska (8950625) Suzanne M Wood (18595714) Magdalena Zarowiecki (3242406) Mert Karakaya (3574748) Brunhilde Wirth (191925) Khalid A Fakhro (18295393) Homa Tajsharghi (456877) Carsten G Bönnemann (18595717) Jenny C Taylor (18595720) Henry Houlden (110428) Genomics England Research Consortium (7845782)
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
author_facet	Alistair T Pagnamenta (18595567) Rauan Kaiyrzhanov (11494177) Yaqun Zou (4678174) Sahar I Da'as (18595570) Reza Maroofian (5237852) Sandra Donkervoort (8411904) Natalia Dominik (17724721) Marlen Lauffer (18595573) Matteo P Ferla (18595576) Andrea Orioli (18595579) Adam Giess (849800) Arianna Tucci (13233424) Christian Beetz (499802) Maryam Sedghi (18595582) Behnaz Ansari (18595585) Rita Barresi (251871) Keivan Basiri (18595588) Andrea Cortese (4599292) Greg Elgar (5184) Miguel A Fernandez-Garcia (18595591) Janice Yip (18595594) A Reghan Foley (16163288) Nicholas Gutowski (3469028) Heinz Jungbluth (3569084) Saskia Lassche (15274039) Tim Lavin (18595597) Carlo Marcelis (206539) Peter Marks (3404351) Chiara Marini-Bettolo (18595600) Livija Medne (3401177) Ali-Reza Moslemi (456876) Anna Sarkozy (672243) Mary M Reilly (9260636) Francesco Muntoni (228210) Francisca Millan (12157194) Colleen C Muraresku (18595603) Anna C Need (18595606) Andrea H Nemeth (18595609) Sarah B Neuhaus (18595612) Fiona Norwood (3569075) Marie O'Donnell (12599998) Mary O’Driscoll (18595615) Julia Rankin (7813010) Sabrina W Yum (18595618) Zarazuela Zolkipli-Cunningham (5234186) Isabell Brusius (16838785) Gilbert Wunderlich (17954830) John C Ambrose (12453972) Prabhu Arumugam (13567201) Emma L Baple (15449710) Marta Bleda (3508925) Freya Boardman-Pretty (18595621) Jeanne M Boissiere (18595624) Christopher R Boustred (18595627) Helen Brittain (18595630) Mark J Caulfield (7948367) Georgia C Chan (18595633) Clare E H Craig (18595636) Louise C Daugherty (18595639) Anna de Burca (18595642) Andrew Devereau (7595366) Rebecca E Foulger (18595645) Tom Fowler (3624713) Pedro Furió-Tarí (3200460) Joanne M Hackett (18595648) Dina Halai (15102816) Angela Hamblin (3746083) Shirley Henderson (3119961) James E Holman (18595651) Tim J P Hubbard (16230509) Kristina ibáñez (18595654) Rob Jackson (9020126) Louise J Jones (16220519) Dalia Kasperaviciute (16277066) Melis Kayikci (239001) Athanasios Kousathanas (493642) Lea Lahnstein (18595657) Kay Lawson (18595660) Sarah E A Leigh (18595663) Ivonne U S Leong (18595666) Javier F Lopez (18595669) Fiona Maleady-Crowe (18595672) Joanne Mason (3520556) Ellen M McDonagh (18595675) Loukas Moutsianas (282004) Michael Mueller (669639) Nirupa Murugaesu (594421) Peter O’Donovan (8564949) Chris A Odhams (18595681) Christine Patch (10875074) Mariana Buongermino Pereira (5126858) Daniel Perez-Gil (6525827) Dimitris Polychronopoulos (558617) John Pullinger (13768447) Tahrima Rahim (18595687) Augusto Rendon (147779) Pablo Riesgo-Ferreiro (10909735) Tim Rogers (6685226) Mina Ryten (347609) Kevin Savage (5229500) Kushmita Sawant (18595690) Richard H Scott (13567189) Afshan Siddiq (151264) Alexander Sieghart (18595693) Damian Smedley (2514) Katherine R Smith (13595329) Samuel C Smith (18595696) Alona Sosinsky (762286) William Spooner (14317) Helen E Stevens (17207455) Alexander Stuckey (4512469) Razvan Sultana (1205) Mélanie Tanguy (4691986) Ellen R A Thomas (18595699) Simon R Thompson (18595702) Carolyn Tregidgo (18595705) Emma Walsh (13558381) Sarah A Watters (18595708) Matthew J Welland (18595711) Eleanor Williams (5144555) Katarzyna Witkowska (8950625) Suzanne M Wood (18595714) Magdalena Zarowiecki (3242406) Mert Karakaya (3574748) Brunhilde Wirth (191925) Khalid A Fakhro (18295393) Homa Tajsharghi (456877) Carsten G Bönnemann (18595717) Jenny C Taylor (18595720) Henry Houlden (110428) Genomics England Research Consortium (7845782)
author_role	author
dc.creator.none.fl_str_mv	Alistair T Pagnamenta (18595567) Rauan Kaiyrzhanov (11494177) Yaqun Zou (4678174) Sahar I Da'as (18595570) Reza Maroofian (5237852) Sandra Donkervoort (8411904) Natalia Dominik (17724721) Marlen Lauffer (18595573) Matteo P Ferla (18595576) Andrea Orioli (18595579) Adam Giess (849800) Arianna Tucci (13233424) Christian Beetz (499802) Maryam Sedghi (18595582) Behnaz Ansari (18595585) Rita Barresi (251871) Keivan Basiri (18595588) Andrea Cortese (4599292) Greg Elgar (5184) Miguel A Fernandez-Garcia (18595591) Janice Yip (18595594) A Reghan Foley (16163288) Nicholas Gutowski (3469028) Heinz Jungbluth (3569084) Saskia Lassche (15274039) Tim Lavin (18595597) Carlo Marcelis (206539) Peter Marks (3404351) Chiara Marini-Bettolo (18595600) Livija Medne (3401177) Ali-Reza Moslemi (456876) Anna Sarkozy (672243) Mary M Reilly (9260636) Francesco Muntoni (228210) Francisca Millan (12157194) Colleen C Muraresku (18595603) Anna C Need (18595606) Andrea H Nemeth (18595609) Sarah B Neuhaus (18595612) Fiona Norwood (3569075) Marie O'Donnell (12599998) Mary O’Driscoll (18595615) Julia Rankin (7813010) Sabrina W Yum (18595618) Zarazuela Zolkipli-Cunningham (5234186) Isabell Brusius (16838785) Gilbert Wunderlich (17954830) John C Ambrose (12453972) Prabhu Arumugam (13567201) Emma L Baple (15449710) Marta Bleda (3508925) Freya Boardman-Pretty (18595621) Jeanne M Boissiere (18595624) Christopher R Boustred (18595627) Helen Brittain (18595630) Mark J Caulfield (7948367) Georgia C Chan (18595633) Clare E H Craig (18595636) Louise C Daugherty (18595639) Anna de Burca (18595642) Andrew Devereau (7595366) Rebecca E Foulger (18595645) Tom Fowler (3624713) Pedro Furió-Tarí (3200460) Joanne M Hackett (18595648) Dina Halai (15102816) Angela Hamblin (3746083) Shirley Henderson (3119961) James E Holman (18595651) Tim J P Hubbard (16230509) Kristina ibáñez (18595654) Rob Jackson (9020126) Louise J Jones (16220519) Dalia Kasperaviciute (16277066) Melis Kayikci (239001) Athanasios Kousathanas (493642) Lea Lahnstein (18595657) Kay Lawson (18595660) Sarah E A Leigh (18595663) Ivonne U S Leong (18595666) Javier F Lopez (18595669) Fiona Maleady-Crowe (18595672) Joanne Mason (3520556) Ellen M McDonagh (18595675) Loukas Moutsianas (282004) Michael Mueller (669639) Nirupa Murugaesu (594421) Peter O’Donovan (8564949) Chris A Odhams (18595681) Christine Patch (10875074) Mariana Buongermino Pereira (5126858) Daniel Perez-Gil (6525827) Dimitris Polychronopoulos (558617) John Pullinger (13768447) Tahrima Rahim (18595687) Augusto Rendon (147779) Pablo Riesgo-Ferreiro (10909735) Tim Rogers (6685226) Mina Ryten (347609) Kevin Savage (5229500) Kushmita Sawant (18595690) Richard H Scott (13567189) Afshan Siddiq (151264) Alexander Sieghart (18595693) Damian Smedley (2514) Katherine R Smith (13595329) Samuel C Smith (18595696) Alona Sosinsky (762286) William Spooner (14317) Helen E Stevens (17207455) Alexander Stuckey (4512469) Razvan Sultana (1205) Mélanie Tanguy (4691986) Ellen R A Thomas (18595699) Simon R Thompson (18595702) Carolyn Tregidgo (18595705) Emma Walsh (13558381) Sarah A Watters (18595708) Matthew J Welland (18595711) Eleanor Williams (5144555) Katarzyna Witkowska (8950625) Suzanne M Wood (18595714) Magdalena Zarowiecki (3242406) Mert Karakaya (3574748) Brunhilde Wirth (191925) Khalid A Fakhro (18295393) Homa Tajsharghi (456877) Carsten G Bönnemann (18595717) Jenny C Taylor (18595720) Henry Houlden (110428) Genomics England Research Consortium (7845782)
dc.date.none.fl_str_mv	2021-01-18T03:00:00Z
dc.identifier.none.fl_str_mv	10.1093/brain/awaa420
dc.relation.none.fl_str_mv	https://figshare.com/articles/journal_contribution/An_ancestral_10-bp_repeat_expansion_in_i_VWA1_i_causes_recessive_hereditary_motor_neuropathy/25877980
dc.rights.none.fl_str_mv	CC BY 4.0 info:eu-repo/semantics/openAccess
dc.subject.none.fl_str_mv	Biological sciences Genetics Biomedical and clinical sciences Neurosciences hereditary motor and sensory neuropathies nerve conduction studies EMG genetics neuropathy whole-genome sequencing
dc.title.none.fl_str_mv	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
dc.type.none.fl_str_mv	Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal
description	<div><p>The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6–83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Brain<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1093/brain/awaa420" target="_blank">https://dx.doi.org/10.1093/brain/awaa420</a></p>
eu_rights_str_mv	openAccess
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identifier_str_mv	10.1093/brain/awaa420
network_acronym_str	Manara2
network_name_str	Manara2
oai_identifier_str	oai:figshare.com:article/25877980
publishDate	2021
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repository.name.fl_str_mv
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rights_invalid_str_mv	CC BY 4.0
spelling	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathyAlistair T Pagnamenta (18595567)Rauan Kaiyrzhanov (11494177)Yaqun Zou (4678174)Sahar I Da'as (18595570)Reza Maroofian (5237852)Sandra Donkervoort (8411904)Natalia Dominik (17724721)Marlen Lauffer (18595573)Matteo P Ferla (18595576)Andrea Orioli (18595579)Adam Giess (849800)Arianna Tucci (13233424)Christian Beetz (499802)Maryam Sedghi (18595582)Behnaz Ansari (18595585)Rita Barresi (251871)Keivan Basiri (18595588)Andrea Cortese (4599292)Greg Elgar (5184)Miguel A Fernandez-Garcia (18595591)Janice Yip (18595594)A Reghan Foley (16163288)Nicholas Gutowski (3469028)Heinz Jungbluth (3569084)Saskia Lassche (15274039)Tim Lavin (18595597)Carlo Marcelis (206539)Peter Marks (3404351)Chiara Marini-Bettolo (18595600)Livija Medne (3401177)Ali-Reza Moslemi (456876)Anna Sarkozy (672243)Mary M Reilly (9260636)Francesco Muntoni (228210)Francisca Millan (12157194)Colleen C Muraresku (18595603)Anna C Need (18595606)Andrea H Nemeth (18595609)Sarah B Neuhaus (18595612)Fiona Norwood (3569075)Marie O'Donnell (12599998)Mary O’Driscoll (18595615)Julia Rankin (7813010)Sabrina W Yum (18595618)Zarazuela Zolkipli-Cunningham (5234186)Isabell Brusius (16838785)Gilbert Wunderlich (17954830)John C Ambrose (12453972)Prabhu Arumugam (13567201)Emma L Baple (15449710)Marta Bleda (3508925)Freya Boardman-Pretty (18595621)Jeanne M Boissiere (18595624)Christopher R Boustred (18595627)Helen Brittain (18595630)Mark J Caulfield (7948367)Georgia C Chan (18595633)Clare E H Craig (18595636)Louise C Daugherty (18595639)Anna de Burca (18595642)Andrew Devereau (7595366)Rebecca E Foulger (18595645)Tom Fowler (3624713)Pedro Furió-Tarí (3200460)Joanne M Hackett (18595648)Dina Halai (15102816)Angela Hamblin (3746083)Shirley Henderson (3119961)James E Holman (18595651)Tim J P Hubbard (16230509)Kristina ibáñez (18595654)Rob Jackson (9020126)Louise J Jones (16220519)Dalia Kasperaviciute (16277066)Melis Kayikci (239001)Athanasios Kousathanas (493642)Lea Lahnstein (18595657)Kay Lawson (18595660)Sarah E A Leigh (18595663)Ivonne U S Leong (18595666)Javier F Lopez (18595669)Fiona Maleady-Crowe (18595672)Joanne Mason (3520556)Ellen M McDonagh (18595675)Loukas Moutsianas (282004)Michael Mueller (669639)Nirupa Murugaesu (594421)Peter O’Donovan (8564949)Chris A Odhams (18595681)Christine Patch (10875074)Mariana Buongermino Pereira (5126858)Daniel Perez-Gil (6525827)Dimitris Polychronopoulos (558617)John Pullinger (13768447)Tahrima Rahim (18595687)Augusto Rendon (147779)Pablo Riesgo-Ferreiro (10909735)Tim Rogers (6685226)Mina Ryten (347609)Kevin Savage (5229500)Kushmita Sawant (18595690)Richard H Scott (13567189)Afshan Siddiq (151264)Alexander Sieghart (18595693)Damian Smedley (2514)Katherine R Smith (13595329)Samuel C Smith (18595696)Alona Sosinsky (762286)William Spooner (14317)Helen E Stevens (17207455)Alexander Stuckey (4512469)Razvan Sultana (1205)Mélanie Tanguy (4691986)Ellen R A Thomas (18595699)Simon R Thompson (18595702)Carolyn Tregidgo (18595705)Emma Walsh (13558381)Sarah A Watters (18595708)Matthew J Welland (18595711)Eleanor Williams (5144555)Katarzyna Witkowska (8950625)Suzanne M Wood (18595714)Magdalena Zarowiecki (3242406)Mert Karakaya (3574748)Brunhilde Wirth (191925)Khalid A Fakhro (18295393)Homa Tajsharghi (456877)Carsten G Bönnemann (18595717)Jenny C Taylor (18595720)Henry Houlden (110428)Genomics England Research Consortium (7845782)Biological sciencesGeneticsBiomedical and clinical sciencesNeuroscienceshereditary motor and sensory neuropathiesnerve conduction studiesEMGgeneticsneuropathywhole-genome sequencing<div><p>The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6–83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Brain<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1093/brain/awaa420" target="_blank">https://dx.doi.org/10.1093/brain/awaa420</a></p>2021-01-18T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1093/brain/awaa420https://figshare.com/articles/journal_contribution/An_ancestral_10-bp_repeat_expansion_in_i_VWA1_i_causes_recessive_hereditary_motor_neuropathy/25877980CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258779802021-01-18T03:00:00Z
spellingShingle	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy Alistair T Pagnamenta (18595567) Biological sciences Genetics Biomedical and clinical sciences Neurosciences hereditary motor and sensory neuropathies nerve conduction studies EMG genetics neuropathy whole-genome sequencing
status_str	publishedVersion
title	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
title_full	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
title_fullStr	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
title_full_unstemmed	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
title_short	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
title_sort	An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy
topic	Biological sciences Genetics Biomedical and clinical sciences Neurosciences hereditary motor and sensory neuropathies nerve conduction studies EMG genetics neuropathy whole-genome sequencing

An ancestral 10-bp repeat expansion in <i>VWA1</i> causes recessive hereditary motor neuropathy

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