{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T18:22:53Z","timestamp":1743618173876,"version":"3.37.3"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007112","name":"University of Cape Town","doi-asserted-by":"publisher","award":["Research Office"],"award-info":[{"award-number":["Research Office"]}],"id":[{"id":"10.13039\/501100007112","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010753","name":"National Health Laboratory Service","doi-asserted-by":"publisher","award":["GRANT004 94623"],"award-info":[{"award-number":["GRANT004 94623"]}],"id":[{"id":"10.13039\/501100010753","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007112","name":"University of Cape Town","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007112","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Int J Legal Med"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sudden unexpected death in infants (SUDI) is a traumatic event for families, and unfortunately its occurrence remains high in many parts of the world. Whilst cause of death is resolved for most cases, others remain undetermined following postmortem investigations. There has been a recognition of the role of genetic testing in unexplained cases, where previous studies have demonstrated the resolution of cases through DNA analyses. Here we present two case reports of SUDI cases admitted to Salt River Mortuary, South Africa, and show that underlying causes of death were determined for both infants using clinical exome sequencing. The first infant was heterozygous for a variant (rs148175795) in <jats:italic>COL6A3<\/jats:italic>, which suggested a bronchopulmonary dysplasia phenotype. This hypothesis led to finding of a second candidate variant in <jats:italic>DMP1<\/jats:italic> (rs142880465), which may contribute towards a digenic\/polygenic mechanism of a more severe phenotype. Histological analysis of retained tissue sections showed an asphyxial mechanism of death, where bronchiolar muscle weakness from an underlying bronchopulmonary dysplasia may have contributed to the asphyxia by affecting respiration. In the second infant, a homozygous variant (rs201340753) was identified in <jats:italic>MASP1<\/jats:italic>, which was heterozygous in each parent, highlighting the value of including parental DNA in genetic studies. Whilst mannose-binding lectin deficiency could not be assessed, it is plausible that this variant may have acted in combination with other risk factors within the triple-risk model to result in sudden death. These results may have genetic implications for family members, and represent possible new candidate variants for molecular autopsies.<\/jats:p>","DOI":"10.1007\/s00414-023-03065-3","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T02:01:31Z","timestamp":1690164091000},"page":"693-700","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical exome sequencing elucidates underlying cause of death in sudden unexpected death of infants: two case reports"],"prefix":"10.1007","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4860-9419","authenticated-orcid":false,"given":"Laura Jane","family":"Heathfield","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorna Jean","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yolande","family":"van der Heyde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itumeleng","family":"Molefe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raj","family":"Ramesar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"3065_CR1","volume-title":"Forensic medicine for lawyers","author":"J Mason","year":"1995","unstructured":"Mason J (1995) Forensic medicine for lawyers, 3rd edn. Butterworths, London","edition":"3"},{"key":"3065_CR2","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1542\/peds.114.1.234","volume":"114","author":"HF Krous","year":"2004","unstructured":"Krous HF, Beckwith JB, Byard RW et al (2004) Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics 114:234\u2013238. https:\/\/doi.org\/10.1542\/peds.114.1.234","journal-title":"Pediatrics"},{"key":"3065_CR3","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1007\/s12024-013-9427-5","volume":"9","author":"L du Toit-Prinsloo","year":"2013","unstructured":"du Toit-Prinsloo L, Dempers J, Verster J et al (2013) Toward a standardized investigation protocol in sudden unexpected deaths in infancy in South Africa: a multicenter study of medico-legal investigation procedures and outcomes. Forensic Sci Med Pathol 9:344\u2013350. https:\/\/doi.org\/10.1007\/s12024-013-9427-5","journal-title":"Forensic Sci Med Pathol"},{"key":"3065_CR4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.2174\/157339610791317241","volume":"6","author":"FR Hauck","year":"2010","unstructured":"Hauck FR, Tanabe KO (2010) International trends in sudden infant death syndrome and other sudden unexpected deaths in infancy: need for better diagnostic standardization. Curr Pediatr Rev 6:95\u2013101. https:\/\/doi.org\/10.2174\/157339610791317241","journal-title":"Curr Pediatr Rev"},{"key":"3065_CR5","doi-asserted-by":"publisher","first-page":"e506","DOI":"10.1542\/peds.2004-0683","volume":"114","author":"SH Opdal","year":"2004","unstructured":"Opdal SH, Rognum TO (2004) The sudden infant death syndrome gene: does it exist? Pediatrics 114:e506\u2013e512. https:\/\/doi.org\/10.1542\/peds.2004-0683","journal-title":"Pediatrics"},{"key":"3065_CR6","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1007\/s00414-020-02337-6","volume":"134","author":"LJ Heathfield","year":"2020","unstructured":"Heathfield LJ, Bhengu W, Louw S et al (2020) Assessment of candidate variants causative of inborn metabolic diseases in SUDI cases in South Africa, and a case report. Int J Legal Med 134:1639\u20131645. https:\/\/doi.org\/10.1007\/s00414-020-02337-6","journal-title":"Int J Legal Med"},{"issue":"04","key":"3065_CR7","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1055\/s-0041-1726471","volume":"11","author":"LJ Heathfield","year":"2021","unstructured":"Heathfield LJ, Watkins H, Martin LJ, Ramesar R (2021) Massively parallel sequencing of 43 arrhythmia genes in a selected SUDI cohort from Cape Town. J Pediatr Genet 11(04):292\u2013297. https:\/\/doi.org\/10.1055\/s-0041-1726471","journal-title":"J Pediatr Genet"},{"key":"3065_CR8","doi-asserted-by":"publisher","first-page":"148","DOI":"10.7196\/SAJCH.2020.v14i3.1720","volume":"14","author":"LJ Heathfield","year":"2020","unstructured":"Heathfield LJ, Martin LJ, Ramesar R (2020) A 5-year retrospective analysis of infant death at Salt River Mortuary, Cape Town. SAJCH South African J Child Heal 14:148\u2013154. https:\/\/doi.org\/10.7196\/SAJCH.2020.v14i3.1720","journal-title":"SAJCH South African J Child Heal"},{"key":"3065_CR9","unstructured":"South African Government (2004) The National Health Act No 61 of 2003. Publicly accessible: https:\/\/www.gov.za\/documents\/national-health-act. Accessed 21 Jul 2023"},{"key":"3065_CR10","doi-asserted-by":"publisher","unstructured":"Mayor S (2016) Low birth weight is associated with increased deaths in infancy and adolescence, shows study. BMJ 353:i2682. https:\/\/doi.org\/10.1136\/bmj.i2682","DOI":"10.1136\/bmj.i2682"},{"key":"#cr-split#-3065_CR11.1","unstructured":"Illumina (2018) Trusight one sequencing panel series reference guide. Document #15046431"},{"key":"#cr-split#-3065_CR11.2","unstructured":"v03. 1-37. Publicly accessible: https:\/\/support.illumina.com\/content\/dam\/illumina-support\/documents\/documentation\/chemistry_documentation\/trusight_one\/trusight-one-sequencing-panel-reference-guide-15046431-03.pdf. Accessed 21 Jul 2023"},{"key":"3065_CR12","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna A, Hanna M, Banks E et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297\u20131303. https:\/\/doi.org\/10.1101\/gr.107524.110","journal-title":"Genome Res"},{"key":"3065_CR13","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S et al (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 Med 17:405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"key":"3065_CR14","doi-asserted-by":"publisher","first-page":"25589","DOI":"10.1074\/jbc.M011637200","volume":"276","author":"T Genetta","year":"2001","unstructured":"Genetta T, Morisaki H, Morisaki T, Holmes EW (2001) A novel bipartite intronic splicing enhancer promotes the inclusion of a mini-exon in the AMP deaminase 1 gene. J Biol Chem 276:25589\u201325597. https:\/\/doi.org\/10.1074\/jbc.M011637200","journal-title":"J Biol Chem"},{"key":"3065_CR15","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/ana.410440124","volume":"44","author":"HT Verzijl","year":"1998","unstructured":"Verzijl HT, van Engelen BG, Luyten JA et al (1998) Genetic characteristics of myoadenylate deaminase deficiency. Ann Neurol 44:140\u2013143. https:\/\/doi.org\/10.1002\/ana.410440124","journal-title":"Ann Neurol"},{"key":"3065_CR16","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/S0960-8966(00)00127-9","volume":"10","author":"M Abe","year":"2000","unstructured":"Abe M, Higuchi I, Morisaki H et al (2000) Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient. Neuromuscul Disord 10:472\u2013477","journal-title":"Neuromuscul Disord"},{"key":"3065_CR17","doi-asserted-by":"publisher","first-page":"5843","DOI":"10.1073\/pnas.91.13.5843","volume":"91","author":"RJ Kelly","year":"1994","unstructured":"Kelly RJ, Ernst LK, Larsen RD et al (1994) Molecular basis for H blood group deficiency in Bombay (Oh) and para-Bombay individuals. Proc Natl Acad Sci U S A 91:5843\u20135847","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3065_CR18","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1542\/peds.2010-0208","volume":"126","author":"J Finsterer","year":"2010","unstructured":"Finsterer J, Ramaciotti C, Wang CH et al (2010) Cardiac findings in congenital muscular dystrophies. Pediatrics 126:538\u2013545. https:\/\/doi.org\/10.1542\/peds.2010-0208","journal-title":"Pediatrics"},{"key":"3065_CR19","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1164\/rccm.201501-0168OC","volume":"192","author":"J Li","year":"2015","unstructured":"Li J, Yu KH, Oehlert J et al (2015) Exome sequencing of neonatal blood spots and the identification of genes implicated in bronchopulmonary dysplasia. Am J Respir Crit Care Med 192:589\u2013596. https:\/\/doi.org\/10.1164\/rccm.201501-0168OC","journal-title":"Am J Respir Crit Care Med"},{"key":"3065_CR20","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3390\/jcm6010004","volume":"6","author":"L Davidson","year":"2017","unstructured":"Davidson L, Berkelhamer S (2017) Bronchopulmonary dysplasia: chronic lung disease of infancy and long-term pulmonary outcomes. J Clin Med 6:4. https:\/\/doi.org\/10.3390\/jcm6010004","journal-title":"J Clin Med"},{"key":"3065_CR21","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1056\/NEJMra067279","volume":"357","author":"E Baraldi","year":"2007","unstructured":"Baraldi E, Filippone M (2007) Chronic lung disease after premature birth. N Engl J Med 357:1946\u20131955. https:\/\/doi.org\/10.1056\/NEJMra067279","journal-title":"N Engl J Med"},{"key":"3065_CR22","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1542\/peds.69.3.301","volume":"69","author":"J Werthammer","year":"1982","unstructured":"Werthammer J, Brown ER, Neff RK, Taeusch HW (1982) Sudden infant death syndrome in infants with bronchopulmonary dysplasia. Pediatrics 69:301\u2013304","journal-title":"Pediatrics"},{"key":"3065_CR23","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1002\/(SICI)1098-1004(1998)12:2<83::AID-HUMU2>3.0.CO;2-P","volume":"12","author":"XQ Song","year":"1998","unstructured":"Song XQ, Fukao T, Watanabe H et al (1998) Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings. Hum Mutat 12:83\u201388. https:\/\/doi.org\/10.1002\/(SICI)1098-1004(1998)12:2%3c83::AID-HUMU2%3e3.0.CO;2-P","journal-title":"Hum Mutat"},{"key":"3065_CR24","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/intimm\/6.4.665","volume":"6","author":"T Sato","year":"1994","unstructured":"Sato T, Endo Y, Matsushita M, Fujita T (1994) Molecular characterization of a novel serine protease involved in activation of the complement system by mannose-binding protein. Int Immunol 6:665\u2013669","journal-title":"Int Immunol"},{"key":"3065_CR25","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1128\/IAI.68.2.688-693.2000","volume":"68","author":"O Neth","year":"2000","unstructured":"Neth O, Jack DL, Dodds AW et al (2000) Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect Immun 68:688\u2013693","journal-title":"Infect Immun"},{"key":"3065_CR26","doi-asserted-by":"publisher","first-page":"e0144633","DOI":"10.1371\/journal.pone.0144633","volume":"10","author":"L Jenny","year":"2015","unstructured":"Jenny L, Dob\u00f3 J, G\u00e1l P, Schroeder V (2015) MASP-1 induced clotting\u2014the first model of prothrombin activation by MASP-1. PLoS One 10:e0144633. https:\/\/doi.org\/10.1371\/journal.pone.0144633","journal-title":"PLoS One"},{"key":"3065_CR27","doi-asserted-by":"publisher","first-page":"8234","DOI":"10.1074\/jbc.M109.065805","volume":"285","author":"M-O Skjoedt","year":"2010","unstructured":"Skjoedt M-O, Hummelshoj T, Palarasah Y et al (2010) A novel mannose-binding lectin\/ficolin-associated protein is highly expressed in heart and skeletal muscle tissues and inhibits complement activation. J Biol Chem 285:8234\u20138243. https:\/\/doi.org\/10.1074\/jbc.M109.065805","journal-title":"J Biol Chem"},{"key":"3065_CR28","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1111\/j.1699-0463.1997.tb05062.x","volume":"105","author":"J Aittoniemi","year":"1997","unstructured":"Aittoniemi J, Rintala E, Miettinen A, Soppi E (1997) Serum mannan-binding lectin (MBL) in patients with infection: clinical and laboratory correlates. APMIS 105:617\u2013622","journal-title":"APMIS"},{"key":"3065_CR29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1136\/adc.78.3.245","volume":"78","author":"J Aittoniemi","year":"1998","unstructured":"Aittoniemi J, Baer M, Soppi E et al (1998) Mannan binding lectin deficiency and concomitant immunodefects. Arch Dis Child 78:245\u2013248. https:\/\/doi.org\/10.1136\/adc.78.3.245","journal-title":"Arch Dis Child"},{"key":"3065_CR30","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1046\/j.1365-3083.1999.00473.x","volume":"49","author":"OB Christiansen","year":"1999","unstructured":"Christiansen OB, Kilpatrick DC, Souter V et al (1999) Mannan-binding lectin deficiency is associated with unexplained recurrent miscarriage. Scand J Immunol 49:193\u2013196","journal-title":"Scand J Immunol"},{"key":"3065_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2015.00107","volume":"6","author":"SM Moscovis","year":"2015","unstructured":"Moscovis SM, Gordon AE, Al Madani OM et al (2015) Virus infections and sudden death in infancy\u202f: the role of interferon- \u03b3. Front Immunol 6:1\u20139. https:\/\/doi.org\/10.3389\/fimmu.2015.00107","journal-title":"Front Immunol"},{"key":"3065_CR32","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/S0379-0738(98)00149-2","volume":"97","author":"DC Kilpatrick","year":"1998","unstructured":"Kilpatrick DC, James VS, Blackwell CC et al (1998) Mannan binding lectin and the sudden infant death syndrome. Forensic Sci Int 97:135\u2013138. https:\/\/doi.org\/10.1016\/S0379-0738(98)00149-2","journal-title":"Forensic Sci Int"},{"key":"3065_CR33","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1159\/000244052","volume":"65","author":"JJ Filiano","year":"1994","unstructured":"Filiano JJ, Kinney HC (1994) A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Neonatology 65:194\u2013197. https:\/\/doi.org\/10.1159\/000244052","journal-title":"Neonatology"}],"container-title":["International Journal of Legal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00414-023-03065-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00414-023-03065-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00414-023-03065-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T11:22:13Z","timestamp":1708168933000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00414-023-03065-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,24]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["3065"],"URL":"https:\/\/doi.org\/10.1007\/s00414-023-03065-3","relation":{},"ISSN":["0937-9827","1437-1596"],"issn-type":[{"type":"print","value":"0937-9827"},{"type":"electronic","value":"1437-1596"}],"subject":[],"published":{"date-parts":[[2023,7,24]]},"assertion":[{"value":"14 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was obtained from the Faculty of Health Science Human Research Ethics Committee at the University of Cape Town (HREC: 445\/2015).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent to participate in this study and to publish the findings was given by the participants or their parents.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The authors declare no competing interests.<b>Reference to pre-print:<\/b> Heathfield, L.J. 2019. Sudden unexpected death in infants: a forensic genetic investigation in a South African cohort. Department Pathology, Faculty of Health Sciences, University of Cape Town. Publicly accessible:","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}