Skip to main content

Advertisement

SpringerLink
Log in

Genetic innovations and our understanding of stillbirth

  • Review
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Stillbirth after 20 weeks gestation happens in 1 in 200 pregnancies and occurs more commonly than neonatal loss and sudden infant death syndrome (SIDs) combined. The stillbirth rate is several times greater in low as opposed to high-resource countries. However, among high-resource countries, although a lower overall stillbirth rate exists, there has been little change for several decades. Molecular genetic technologies are emerging as important contributors to our understanding of stillbirth. Initially, genetic etiologies included alterations in chromosome number or structure such as aneuploidy and microduplications and deletions. More recently, next-generation sequencing analysis in two genetic conditions, Smith Lemli Optiz Syndrome (SLOs) and the channelopathy disorders (such as long QT syndrome (LQTS)) provide examples into the association of pathogenic gene variants with stillbirth. Although these specific conditions individually account for only a small number of stillbirths, investigating these disorders provides a new and innovative approach for further understanding genetic contributors to adverse pregnancy outcomes. Our knowledge of the role of genetic disease as an etiology for stillbirth is elementary. Genomic interrogation of maternal–fetal genotypes, gene–gene, and genotype–environment interaction is lacking in stillbirth research. At the DNA sequence level, further investigation of variants of unknown significance is an opportunity for exploration of biologic pathways of importance to pregnancy loss. This review concentrates on SLO as an example of a single gene disorder with a high carrier but low affected liveborn proband rate. The channelopathy disorders are included as initial examples of genetic conditions with variable presentation including an association with sudden infant death syndrome. Highlighted are the challenges when numerous genes and variants are involved, and the task of assigning pathogenicity. The advantages and limitations of genetic evaluations are presented and avenues for further research considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abuelo DN, Tint GS, Kelley R, Batta AK, Shefer S, Salen G (1995) Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols. Am J Med Genet 56(3):281–285

    CAS  PubMed  Google Scholar 

  • Ackerman MJ (2004) Cardiac channelopathies: it's in the genes. Nat Med 10(5):463–464

    CAS  PubMed  Google Scholar 

  • Ackerman K, Creery D (2003) Cardiorespiratory arrest in children. Clin Evid (9):341–349

    Google Scholar 

  • Barnett (2007) – personal communication

  • Baruteau AE, Probst V, Abriel H (2015) Inherited progressive cardiac conduction disorders. Curr Opin Cardiol 30(1):33–39

    PubMed  Google Scholar 

  • Baruteau AE, Tester DJ, Kapplinger JD, Ackerman MJ, Behr ER (2017) Sudden infant death syndrome and inherited cardiac conditions. Nat Rev Cardiol 14(12):715–726

    PubMed  Google Scholar 

  • Battaile KP, Battaile BC, Merkens LS, Maslen CL, Steiner RD (2001) Carrier frequency of the common mutation IVS8-1G>C in DHCR7 and estimate of the expected incidence of Smith-Lemli-Opitz syndrome. Mol Genet Metab 72(1):67–71

    CAS  PubMed  Google Scholar 

  • Boland MR, Tatonetti NP (2016) Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J 16(5):411–429

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bose CL, Bauserman M, Goldenberg RL, Goudar SS, McClure EM, Pasha O, Carlo WA, Garces A, Moore JL, Miodovnik M, Koso-Thomas M (2015) The Global Network Maternal Newborn Health Registry: a multi-national, community-based registry of pregnancy outcomes. Reprod Health 12(Suppl 2):S1

    PubMed  PubMed Central  Google Scholar 

  • Buxton AE, Calkins H, Callans DJ, DiMarco JP, Fisher JD, Greene HL, Haines DE, Hayes DL, Heidenreich PA, Miller JM, Poppas A, Prystowsky EN, Schoenfeld MH, Zimetbaum PJ, Heidenreich PA, Goff DC, Grover FL, Malenka DJ, Peterson ED, Radford MJ, Redberg RF, C. American College of and S. American Heart Association Task Force on Clinical Data (2006) ACC/AHA/HRS 2006 key data elements and definitions for electrophysiological studies and procedures: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology). J Am Coll Cardiol 48(11):2360–2396

    PubMed  Google Scholar 

  • Campuzano O, Allegue C, Fernandez A, Iglesias A, Brugada R (2015) Determining the pathogenicity of genetic variants associated with cardiac channelopathies. Sci Rep 5:7953

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crotti L, Tester DJ, White WM, Bartos DC, Insolia R, Besana A, Kunic JD, Will ML, Velasco EJ, Bair JJ, Ghidoni A, Cetin I, Van Dyke DL, Wick MJ, Brost B, Delisle BP, Facchinetti F, George AL, Schwartz PJ, Ackerman MJ (2013) Long QT syndrome-associated mutations in intrauterine fetal death. JAMA 309(14):1473–1482

    CAS  PubMed  Google Scholar 

  • Ciara E, Popowska E, Piekutowska-Abramczuk D, Jurkiewicz D, Borucka-Mankiewicz M, Kowalski P, Goryluk-Kozakiewicz B, Nowaczyk MJ, Krajewska-Walasek M (2006) SLOS carrier frequency in Poland as determined by screening for Trp151X and Val326Leu DHCR7 mutations. Eur J Med Genet 49(6):499–504

    CAS  PubMed  Google Scholar 

  • de Bernis L, Kinney MV, Stones W, Ten Hoope-Bender P, Vivio D, Leisher SH, Bhutta ZA, Gulmezoglu M, Mathai M, Belizan JM, Franco L, McDougall L, Zeitlin J, Malata A, Dickson KE, Lawn JE, g. Lancet Ending Preventable Stillbirths Series study, G. Lancet Ending Preventable Stillbirths Series Advisory (2016) Stillbirths: ending preventable deaths by 2030. Lancet 387(10019):703–716

    PubMed  Google Scholar 

  • Drury S, Williams H, Trump N, Boustred C, Gosgene, Lench N, Scott RH, Chitty LS (2015) Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn 35(10):1010–1017

    CAS  PubMed  Google Scholar 

  • Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS (2013) A systematic approach to assessing the clinical significance of genetic variants. Clin Genet 84(5):453–463

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrante L, Opdal SH, Vege A, Rognum T (2010) Cytokine gene polymorphisms and sudden infant death syndrome. Acta Paediatr 99(3):384–388

    CAS  PubMed  Google Scholar 

  • Ferrante L, Rognum TO, Vege A, Nygard S, Opdal SH (2016) Altered gene expression and possible immunodeficiency in cases of sudden infant death syndrome. Pediatr Res 80(1):77–84

    CAS  PubMed  Google Scholar 

  • Filiano JJ, Kinney HC (1994) A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Biol Neonate 65(3–4):194–197

    CAS  PubMed  Google Scholar 

  • Froen JF, Friberg IK, Lawn JE, Bhutta ZA, Pattinson RC, Allanson ER, Flenady V, McClure EM, Franco L, Goldenberg RL, Kinney MV, Leisher SH, Pitt C, Islam M, Khera A, Dhaliwal L, Aggarwal N, Raina N, Temmerman M, Lancet Ending Preventable Stillbirths Series study (2016) Stillbirths: progress and unfinished business. Lancet 387(10018):574–586

    PubMed  Google Scholar 

  • Gibbins KJ, Reddy UM, Saade GR, Goldenberg RL, Dudley DJ, Parker CB, Thorsten V, Pinar H, Bukowski R, Hogue CJ, Silver RM (2018) Smith-Lemli-Opitz mutations in unexplained stillbirths. Am J Perinatol 35(10):936–939

    PubMed  PubMed Central  Google Scholar 

  • Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ (2018a) Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing. Circulation 137(6):619–630

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giudicessi JR, Wilde AAM, Ackerman MJ (2018b) The genetic architecture of long QT syndrome: a critical reappraisal. Trends Cardiovasc Med 28(7):453–464

    PubMed  PubMed Central  Google Scholar 

  • Gravett MG, Rubens CE, Nunes TM, G. R. Group (2010) Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 10(Suppl 1):S2

    PubMed  PubMed Central  Google Scholar 

  • Hoyert DL, Gregory EC (2016) Cause of fetal death: data from the fetal death report, 2014. Natl Vital Stat Rep 65(7):1–25

    PubMed  Google Scholar 

  • Irons M, Elias ER, Salen G, Tint GS, Batta AK (1993) Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 341(8857):1414

    CAS  PubMed  Google Scholar 

  • Ishikawa S, Yamada T, Kuwata T, Morikawa M, Yamada T, Matsubara S, Minakami H (2013) Fetal presentation of long QT syndrome–evaluation of prenatal risk factors: a systematic review. Fetal Diagn Ther 33(1):1–7

    PubMed  Google Scholar 

  • Kadish AH, Greenland P, Limacher MC, Frishman WH, Daugherty SA, Schwartz JB (2004) Estrogen and progestin use and the QT interval in postmenopausal women. Ann Noninvasive Electrocardiol 9(4):366–374

    PubMed  PubMed Central  Google Scholar 

  • Kelley RI, Herman GE (2001) Inborn errors of sterol biosynthesis. Annu Rev Genomics Hum Genet 2:299–341

    CAS  PubMed  Google Scholar 

  • Korteweg FJ, Gordijn SJ, Timmer A, Erwich JJ, Bergman KA, Bouman K, Ravise JM, Heringa MP, Holm JP (2006) The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement. BJOG 113(4):393–401

    CAS  PubMed  Google Scholar 

  • Korteweg FJ, Erwich JJ, Timmer A, van der Meer J, Ravise JM, Veeger NJ, Holm JP (2012) Evaluation of 1025 fetal deaths: proposed diagnostic workup. Am J Obstet Gynecol 206(1): 53.e51–53 e12

  • Lanthaler B, Steichen-Gersdorf E, Kollerits B, Zschocke J, Witsch-Baumgartner M (2013) Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations. Eur J Hum Genet 21(3):286–293

    CAS  PubMed  Google Scholar 

  • Lawn JE, Gravett MG, Nunes TM, Rubens CE, Stanton C, G. R. Group (2010) Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data. BMC Pregnancy Childbirth 10(Suppl 1):S1

    PubMed  PubMed Central  Google Scholar 

  • Lawn JE, Blencowe H, Waiswa P, Amouzou A, Mathers C, Hogan D, Flenady V, Froen JF, Qureshi ZU, Calderwood C, Shiekh S, Jassir FB, You D, McClure EM, Mathai M, Cousens S, g. Lancet Ending Preventable Stillbirths Series study, g. Lancet Stillbirth Epidemiology investigator (2016) Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet 387(10018):587–603

    PubMed  Google Scholar 

  • Lazarin GA, Haque IS, Evans EA, Goldberg JD (2017) Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates. Prenat Diagn 37(4):350–355

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312(18):1880–1887

    PubMed  PubMed Central  Google Scholar 

  • Leisher SH, Teoh Z, Reinebrant H, Allanson E, Blencowe H, Erwich JJ, Froen JF, Gardosi J, Gordijn S, Gulmezoglu AM, Heazell AE, Korteweg F, Lawn J, McClure EM, Pattinson R, Smith GC, Tuncalp, Wojcieszek AM, Flenady V (2016) Seeking order amidst chaos: a systematic review of classification systems for causes of stillbirth and neonatal death, 2009–2014. BMC Pregnancy Childbirth 16(1):295

    PubMed  PubMed Central  Google Scholar 

  • Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ (1998) Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 97(22):2237–2244

    CAS  PubMed  Google Scholar 

  • Loeffler J, Witsch-Baumgartner M, Menze HJ, Kraft HG, Utermann G (2001) Carrier frequencies of DHCR7 mutation in WestAustria indicate that Smith-Lemli-Opitz syndrome is among the most common autosomal recessive disorders. Eur J Hum Genet 9:S282

    Google Scholar 

  • Lord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, Prigmore E, Keelagher R, Best SK, Carey GK, Mellis R, Robart S, Berry IR, Chandler KE, Cilliers D, Cresswell L, Edwards SL, Gardiner C, Henderson A, Holden ST, Homfray T, Lester T, Lewis RA, Newbury-Ecob R, Prescott K, Quarrell OW, Ramsden SC, Roberts E, Tapon D, Tooley MJ, Vasudevan PC, Weber AP, Wellesley DG, Westwood P, White H, Parker M, Williams D, Jenkins L, Scott RH, Kilby MD, Chitty LS, Hurles ME, Maher ER, G. Prenatal Assessment of and C (2019) Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393(10173):747–757

    CAS  PubMed  PubMed Central  Google Scholar 

  • Modell SM, Lehmann MH (2006) The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med 8(3):143–155

    CAS  PubMed  Google Scholar 

  • Munroe PB, Addison S, Abrams DJ, Sebire NJ, Cartwright J, Donaldson I, Cohen MM, Mein C, Tinker A, Harmer SC, Aziz Q, Terry A, Struebig M, Warren HR, Vadgama B, Fowler DJ, Peebles D, Taylor AM, Lally PJ, Thayyil S (2018) Postmortem genetic testing for cardiac ion channelopathies in stillbirths. Circ Genom Precis Med 11(1):e001817

    CAS  PubMed  Google Scholar 

  • Nowaczyk MJ, Irons MB (2012) Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet 160C(4):250–262

    PubMed  Google Scholar 

  • Nowaczyk MJ, Waye JS, Douketis JD (2006) DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: where are the patients? Am J Med Genet A 140(19):2057–2062

    PubMed  Google Scholar 

  • Odening KE, Koren G, Kirk M (2016) Normalization of QT interval duration in a long QT syndrome patient during pregnancy and the postpartum period due to sex hormone effects on cardiac repolarization. HeartRhythm Case Rep 2(3):223–227

    PubMed  PubMed Central  Google Scholar 

  • Opdal SH, Rognum TO (2011) Gene variants predisposing to SIDS: current knowledge. Forensic Sci Med Pathol 7(1):26–36

    PubMed  Google Scholar 

  • Opitz JM (1994) RSH/SLO (“Smith-Lemli-Opitz”) syndrome: historical, genetic, and developmental considerations. Am J Med Genet 50(4):344–346

    CAS  PubMed  Google Scholar 

  • Opitz JM, Gilbert-Barness E, Ackerman J, Lowichik A (2002) Cholesterol and development: the RSH (“Smith-Lemli-Opitz”) syndrome and related conditions. Pediatr Pathol Mol Med 21(2):153–181

    CAS  PubMed  Google Scholar 

  • Page JM, Christiansen-Lindquist L, Thorsten V, Parker CB, Reddy UM, Dudley DJ, Saade GR, Coustan D, Rowland Hogue CJ, Conway D, Bukowski R, Pinar H, Heuser CC, Gibbins KJ, Goldenberg RL, Silver RM (2017) Diagnostic tests for evaluation of stillbirth: results from the stillbirth collaborative research network. Obstet Gynecol 129(4):699–706

    CAS  PubMed  Google Scholar 

  • Priori SG, Napolitano C, Vicentini A (2003) Inherited arrhythmia syndromes: applying the molecular biology and genetic to the clinical management. J Interv Card Electrophysiol 9(2):93–101

    PubMed  Google Scholar 

  • Quelin C, Loget P, Verloes A, Bazin A, Bessieres B, Laquerriere A, Patrier S, Grigorescu R, Encha-Razavi F, Delahaye S, Jouannic JM, Carbonne B, D’Herve D, Aubry MC, Mace G, Harvey T, Ville Y, Viot G, Joye N, Odent S, Attie-Bitach T, Wolf C, Chevy F, Benlian P, Gonzales M (2012) Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. Eur J Med Genet 55(2):81–90

    PubMed  Google Scholar 

  • Quinlan-Jones E, Lord J, Williams D, Hamilton S, Marton T, Eberhardt RY, Rinck G, Prigmore E, Keelagher R, McMullan DJ, Maher ER, Hurles ME, Kilby MD (2019) Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. Genet Med 21(5):1065–1073

    CAS  PubMed  Google Scholar 

  • Reddy UM, Page GP, Saade GR, Silver RM, Thorsten VR, Parker CB, Pinar H, Willinger M, Stoll BJ, Heim-Hall J, Varner MW, Goldenberg RL, Bukowski R, Wapner RJ, Drews-Botsch CD, O’Brien BM, Dudley DJ, Levy B, Network NSCR (2012) Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185–2193

    CAS  PubMed  PubMed Central  Google Scholar 

  • Refsgaard L, Holst AG, Sadjadieh G, Haunso S, Nielsen JB, Olesen MS (2012) High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet 20(8):905–908

    CAS  PubMed  PubMed Central  Google Scholar 

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (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(5):405–424

    PubMed  PubMed Central  Google Scholar 

  • Sahlin E, Green A, Gustavsson P, Lieden A, Nordenskjold M, Papadogiannakis N, Pettersson K, Nilsson D, Jonasson J, Iwarsson E (2019) Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. PLoS ONE 14(1):e0210017

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schoen E, Norem C, O’Keefe J, Krieger R, Walton D, To TT (2003) Maternal serum unconjugated estriol as a predictor for Smith-Lemli-Opitz syndrome and other fetal conditions. Obstet Gynecol 102(1):167–172

    CAS  PubMed  Google Scholar 

  • Schwartz PJ (1976) Cardiac sympathetic innervation and the sudden infant death syndrome. A possible pathogenetic link. Am J Med 60(2):167–172

    CAS  PubMed  Google Scholar 

  • Schwartz PJ (2004) Stillbirths, sudden infant deaths, and long-QT syndrome: puzzle or mosaic, the pieces of the Jigsaw are being fitted together. Circulation 109(24):2930–2932

    PubMed  Google Scholar 

  • Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R (2000) A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 343(4):262–267

    CAS  PubMed  Google Scholar 

  • Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, Robinson JL, Goldenberg I, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L (2007) Long QT syndrome and pregnancy. J Am Coll Cardiol 49(10):1092–1098

    PubMed  Google Scholar 

  • Shamseldin HE, Kurdi W, Almusafri F, Alnemer M, Alkaff A, Babay Z, Alhashem A, Tulbah M, Alsahan N, Khan R, Sallout B, Al Mardawi E, Seidahmed MZ, Meriki N, Alsaber Y, Qari A, Khalifa O, Eyaid W, Rahbeeni Z, Kurdi A, Hashem M, Alshidi T, Al-Obeid E, Abdulwahab F, Ibrahim N, Ewida N, El-Akouri K, Al Mulla M, Ben-Omran T, Pergande M, Cirak S, Al Tala S, Shaheen R, Faqeih E, Alkuraya FS (2018) Molecular autopsy in maternal–fetal medicine. Genet Med 20(4):420–427

    CAS  PubMed  Google Scholar 

  • Sims D, Sudbery I, Ilott NE, Heger A, Ponting CP (2014) Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet 15(2):121–132

    CAS  PubMed  Google Scholar 

  • Smith DW, Lemli L, Opitz JM (1964) A newly recognized syndrome of multiple congenital anomalies. J Pediatr 64:210–217

    CAS  PubMed  Google Scholar 

  • Solca C, Pandit B, Yu H, Tint GS, Patel SB (2007) Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse. Mol Genet Metab 91(1):7–14

    CAS  PubMed  PubMed Central  Google Scholar 

  • Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102(10):1178–1185

    CAS  PubMed  Google Scholar 

  • Strauss JF 3rd, Romero R, Gomez-Lopez N, Haymond-Thornburg H, Modi BP, Teves ME, Pearson LN, York TP, Schenkein HA (2018) Spontaneous preterm birth: advances toward the discovery of genetic predisposition. Am J Obstet Gynecol 218(3):294–314.e292

    PubMed  Google Scholar 

  • Tester DJ, Ackerman MJ (2005) Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 67(3):388–396

    CAS  PubMed  Google Scholar 

  • Waterham HR, Hennekam RC (2012) Mutational spectrum of Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet 160C(4):263–284

    PubMed  Google Scholar 

  • Waye JS, Nakamura LM, Eng B, Hunnisett L, Chitayat D, Costa T, Nowaczyk MJ (2002) Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. J Med Genet 39(6):E31

    CAS  PubMed  PubMed Central  Google Scholar 

  • Witsch-Baumgartner M, Loffler J, Utermann G (2001) Mutations in the human DHCR7 gene. Hum Mutat 17(3):172–182

    CAS  PubMed  Google Scholar 

  • Witsch-Baumgartner M, Gruber M, Kraft HG, Rossi M, Clayton P, Giros M, Haas D, Kelley RI, Krajewska-Walasek M, Utermann G (2004) Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome. J Med Genet 41(8):577–584

    CAS  PubMed  Google Scholar 

  • Wright BS, Nwokoro NA, Wassif CA, Porter FD, Waye JS, Eng B, Nowaczyk MJ (2003) Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G>C mutation in African Americans. Am J Med Genet A 120A(1):139–141

    PubMed  Google Scholar 

  • Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M, Patel A, Boerwinkle E, Beaudet AL, Lupski JR, Plon SE, Gibbs RA, Eng CM (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312(18):1870–1879

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Lee MH, Starck L, Elias ER, Irons M, Salen G, Patel SB, Tint GS (2000) Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet 9(9):1385–1391

    CAS  PubMed  Google Scholar 

  • Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, Schwartz PJ, Vincent GM, Priori SG, Benhorin J, Towbin JA, Robinson L, Andrews ML, Napolitano C, Timothy K, Zhang L, Medina A, Q. T. S. R. International Long (2003) Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol 42(1):103–109

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 01770, USA

    Louise Wilkins-Haug

Authors
  1. Louise Wilkins-Haug
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Louise Wilkins-Haug.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wilkins-Haug, L. Genetic innovations and our understanding of stillbirth. Hum Genet 139, 1161–1172 (2020). https://doi.org/10.1007/s00439-020-02146-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-020-02146-2

Search

Navigation