{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:46:35Z","timestamp":1775666795494,"version":"3.50.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010221","name":"Higher Education Commision, Pakistan","doi-asserted-by":"publisher","award":["IRSIP 52 BMS 22"],"award-info":[{"award-number":["IRSIP 52 BMS 22"]}],"id":[{"id":"10.13039\/501100010221","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurol Sci"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hereditary sensory and autonomic neuropathies (HSANs) are rare inherited disorders characterized by sensory and autonomic nerve dysfunction classified into eight subtypes. HSAN-VI (OMIM: 614653) is an autosomal recessive subtype which manifests severe pain insensitivity, neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development and autonomic abnormalities. Pathogenic variants in the\n                      <jats:italic>DST<\/jats:italic>\n                      gene, which encodes dystonin have been identified as the underlying cause of HSAN-VI. Thus far, only 15 HSAN-VI patients associated with 11\n                      <jats:italic>DST<\/jats:italic>\n                      variants, mostly compound heterozygous, have been identified in the literature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We aimed clinical and molecular genetic characterization of a Pakistani family presenting a phenotype consistent with HSAN-VI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The proband\u2019s DNA was subjected to whole exome sequencing and homozygosity mapping. Sanger sequencing was used to test variant segregation in the available members of the family. Pathogenicity and deleterious effects of the identified variant on the protein function was tested through bioinformatic in silico prediction tools. Further, we collected clinical and molecular information for all 15 patients reported in the literature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a novel missense\n                      <jats:italic>DST<\/jats:italic>\n                      variant NM_001374736.1:c.21,899\u00a0A\u2009&gt;\u2009G; p.(Asp7300Gly), classified as a VUS, in autosomal recessive pattern of inheritance in the family. We summarized and compared clinical manifestations and mutation data of previously reported HSAN-VI patients along with those presented in the current study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings expand the mutation spectrum of\n                      <jats:italic>DST-<\/jats:italic>\n                      associated HSAN-VI potentially adding to its pathophysiology. To our knowledge, this is the second report of a homozygous missense\n                      <jats:italic>DST<\/jats:italic>\n                      variant overall, and first report of HSAN-VI from Pakistan.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10072-025-08424-z","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T06:00:00Z","timestamp":1757656800000},"page":"6815-6822","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rare autosomal recessive hereditary sensory and autonomic neuropathy type VI in a Pakistani family caused by a novel DST variant"],"prefix":"10.1007","volume":"46","author":[{"given":"Riaz","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Zamani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3894-3085","authenticated-orcid":false,"given":"Muhammad","family":"Naeem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"8424_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11910-019-0974-3","volume":"19","author":"C Schwartzlow","year":"2019","unstructured":"Schwartzlow C, Kazamel M (2019) Hereditary sensory and autonomic neuropathies: adding more to the classification. Curr Neurol Neurosci Rep 19:1\u201311","journal-title":"Curr Neurol Neurosci Rep"},{"issue":"1","key":"8424_CR2","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000389","volume":"6","author":"A Lynch-Godrei","year":"2020","unstructured":"Lynch-Godrei A, Kothary R (2020) HSAN-VI: a spectrum disorder based on dystonin isoform expression. Neurol Genet 6(1):e389","journal-title":"Neurol Genet"},{"key":"8424_CR3","doi-asserted-by":"crossref","unstructured":"Edvardson S, Cinnamon Y, Jalas C, Shaag A, Maayan C, Axelrod FB, Elpeleg O (2012) Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Annals of neurology, 71(4), pp 569\u2013572","DOI":"10.1002\/ana.23524"},{"issue":"4","key":"8424_CR4","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1083\/jcb.200012098","volume":"154","author":"CL Leung","year":"2001","unstructured":"Leung CL, Zheng M, Prater SM, Liem RK (2001) The BPAG1 locus: alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles. J Cell Biol 154(4):691\u2013698","journal-title":"J Cell Biol"},{"key":"8424_CR5","doi-asserted-by":"crossref","unstructured":"Horie M, Yoshioka N, Takebayashi H (2017) September BPAG1 in muscles: structure and function in skeletal, cardiac and smooth muscle. Seminars in cell & developmental biology vol. 69 pp 26\u201333. Academic Press","DOI":"10.1016\/j.semcdb.2017.07.016"},{"key":"8424_CR6","doi-asserted-by":"crossref","unstructured":"K\u00fc\u00fcnzli K, Favre B, Chofflon M, Borradori L (2016) One gene but different proteins and diseases: The complexity of dystonin and bullous pemphigoid antigen 1. Experimental Dermatology, 25(1), pp 10\u201316","DOI":"10.1111\/exd.12877"},{"issue":"5","key":"8424_CR7","first-page":"405","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Sci 17(5):405\u2013423","journal-title":"Genet Sci"},{"key":"8424_CR8","doi-asserted-by":"crossref","unstructured":"Quinodoz M, Peter VG, Bedoni N, Bertrand R, Cisarova B, Salmaninejad K, Sepahi A, Rodrigues N, Piran R, Mojarrad M, M. and, Pasdar A (2021) AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data. Nature communications, 12(1) p 518","DOI":"10.1038\/s41467-020-20584-4"},{"issue":"9","key":"8424_CR9","first-page":"841","volume":"13","author":"H Hamamy","year":"2011","unstructured":"Hamamy H, Antonarakis SE, Cavalli-Sforza LL, Temtamy S, Romeo G, Kate T, Bennett LP, Shaw RL, Megarbane A, Van Duijn A, C. and, Bathija H (2011) Consanguineous marriages, pearls and perils: Geneva international consanguinity workshop report. Genet Sci 13(9):841\u2013847","journal-title":"Genet Sci"},{"issue":"22","key":"8424_CR10","doi-asserted-by":"publisher","first-page":"2132","DOI":"10.1212\/WNL.0000000000003992","volume":"88","author":"F Manganelli","year":"2017","unstructured":"Manganelli F, Parisi S, Nolano M, Tao F, Paladino S, Pisciotta C, Tozza S, Nesti C, Rebelo AP, Provitera V, Santorelli FM (2017) Novel mutations in dystonin provide clues to the pathomechanisms of HSAN-VI. Neurology 88(22):2132\u20132140","journal-title":"Neurology"},{"issue":"10","key":"8424_CR11","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1002\/ajmg.a.38367","volume":"173","author":"G Cappuccio","year":"2017","unstructured":"Cappuccio G, Pinelli M, Torella A, Alagia M, Auricchio R, Staiano A, Nigro V, TUDP, Brunetti-Pierri N (2017) Expanding the phenotype of DST\u2010related disorder: a case report suggesting a genotype\/phenotype correlation. Am J Med Genet A 173(10):2743\u20132746","journal-title":"Am J Med Genet A"},{"key":"8424_CR12","doi-asserted-by":"crossref","unstructured":"Fortugno P, Angelucci F, Cestra G, Camerota L, Ferraro AS, Cordisco S, Uccioli L, Castiglia D, De Angelis B, Kurth I, Kornak U (2019) Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI. Hum Mutat, 40(1), pp 106\u2013114","DOI":"10.1002\/humu.23678"},{"key":"8424_CR13","doi-asserted-by":"crossref","unstructured":"Jin JY, Wu PF, He JQ, Fan LL, Yuan ZZ, Pang XY, Tang JY, Zhang LY (2020) Novel compound heterozygous DST variants causing hereditary sensory and autonomic neuropathies VI in twins of a Chinese family. Front Genet 11 p 492","DOI":"10.3389\/fgene.2020.00492"},{"issue":"4","key":"8424_CR14","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1002\/ajmg.a.62609","volume":"188","author":"RP Sakaria","year":"2022","unstructured":"Sakaria RP, Fonville MP, Peravali S, Zaveri PG, Mroczkowski HJ, Caron E, Weems MF (2022) A novel variant in the dystonin gene causing hereditary sensory autonomic neuropathy type VI in a male infant: case report and literature review. Am J Med Genet Part A 188(4):1245\u20131250","journal-title":"Am J Med Genet Part A"},{"key":"8424_CR15","doi-asserted-by":"crossref","unstructured":"Peringassery Sateesh L, Chitamanni P, Akinsanmi D, Ghosh S, Pavlakis SG, Reznikov A (2024) Hereditary sensory autonomic neuropathy type VI in the age of genetic testing. Ann Child Neurol Soc, 2: 290\u2013294","DOI":"10.1002\/cns3.20085"},{"key":"8424_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2164-7-306","volume":"7","author":"S Subramanian","year":"2006","unstructured":"Subramanian S, Kumar S (2006) Evolutionary anatomies of positions and types of disease-associated and neutral amino acid mutations in the human genome. BMC Genomics 7:1\u20139","journal-title":"BMC Genomics"},{"key":"8424_CR17","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.molcel.2011.10.013","volume":"44","author":"A Helmrich","year":"2011","unstructured":"Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44:966\u2013977. https:\/\/doi.org\/10.1016\/j.molcel.2011.10.013","journal-title":"Mol Cell"},{"key":"8424_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.559998","volume":"12","author":"I Lopes","year":"2021","unstructured":"Lopes I, Altab G, Raina P, De Magalh\u00e3es JP (2021) Gene size matters: an analysis of gene length in the human genome. Front Genet 12:559998","journal-title":"Front Genet"}],"container-title":["Neurological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10072-025-08424-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10072-025-08424-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10072-025-08424-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:41:09Z","timestamp":1764895269000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10072-025-08424-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":18,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["8424"],"URL":"https:\/\/doi.org\/10.1007\/s10072-025-08424-z","relation":{},"ISSN":["1590-1874","1590-3478"],"issn-type":[{"value":"1590-1874","type":"print"},{"value":"1590-3478","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]},"assertion":[{"value":"25 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Ethics Review Committee of the University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from the enrolled family to participate in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Informed consent was obtained from the enrolled families to allow publication of the clinical and diagnostic information collected in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare they have no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}