Download PDF
Am J Perinatol 2018; 35(10): 936-939
DOI: 10.1055/s-0038-1626705
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Smith–Lemli–Opitz Mutations in Unexplained Stillbirths

Karen J. Gibbins
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, Utah
,
Uma M. Reddy
2   Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
,
George R. Saade
3   Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Robert L. Goldenberg
4   Department of Obstetrics and Gynecology, Columbia University School of Medicine, New York, New York
,
Donald J. Dudley
5   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia
,
Corette B. Parker
6   RTI International, Durham, North Carolina
,
Vanessa Thorsten
6   RTI International, Durham, North Carolina
,
Halit Pinar
7   Department of Pediatric and Developmental Pathology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
,
Radek Bukowski
8   Department of Women's Health, University of Texas–Austin, Austin, Texas
,
Carol J. Hogue
9   Department of Epidemiology, Emory University, Atlanta, Georgia
,
Robert M. Silver
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, Utah
› Author Affiliations Funding This study was supported by grants (HD45925, HD45944, HD45952, HD45953, HD45954, and HD45925) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Further Information

Publication History

15 November 2017

20 December 2017

Publication Date:
12 February 2018 (online)

    Permissions and Reprints

Abstract

Objective Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7-dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths.

Study Design Prospective, multicenter, population-based case–control study of all stillbirths and a representative sample of live births enrolled in five geographic areas. Cases with stillbirth due to obstetric complications, infection, or aneuploidy, and those with poor quality deoxyribonucleic acid (DNA) were excluded. DNA was extracted from placental tissue stored at –80°C, and exons 3 to 9 of the DCHR7 gene were amplified, purified, and subjected to bidirectional sequencing to identify mutations.

Results One-hundred forty four stillbirths were unexplained and had adequate DNA for analysis. Nine stillbirths of 139 (6.5%) had a single mutation in one allele in coding exons 3 to 9 of DHCR7 (Table 1). One case (0.7%) was a compound heterozygote for mutations in exons 3 to 9 of DHCR7; this fetus had no clinical or histologic features of SLOS.

Conclusion We detected SLOS mutations in only 0.7% of stillbirths. This does not support a strong association between unrecognized DHCR7 mutations and stillbirth.

Keywords

Smith–Lemli–Opitz - stillbirth - genetic syndrome - cholesterol biosynthesis

Note

The comments and views of the authors do not necessarily represent the views of the NICHD.


 

  • References

  • 1 Quélin C, Loget P, Verloes A. , et al. Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. Eur J Med Genet 2012; 55 (02) 81-90
    CrossrefPubMedGoogle Scholar
  • 2 Opitz JM, Gilbert-Barness E, Ackerman J, Lowichik A. Cholesterol and development: the RSH (“Smith-Lemli-Opitz”) syndrome and related conditions. Pediatr Pathol Mol Med 2002; 21 (02) 153-181
    CrossrefPubMedGoogle Scholar
  • 3 Opitz JM. A little cholesterol in time..... Clin Invest Med 2001; 24 (06) 318-320
    PubMedGoogle Scholar
  • 4 Waye JS, Nakamura LM, Eng B. , et al. Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. J Med Genet 2002; 39 (06) E31
    CrossrefPubMedGoogle Scholar
  • 5 Nowaczyk MJ, Nakamura LM, Eng B, Porter FD, Waye JS. Frequency and ethnic distribution of the common DHCR7 mutation in Smith-Lemli-Opitz syndrome. Am J Med Genet 2001; 102 (04) 383-386
    CrossrefPubMedGoogle Scholar
  • 6 Nowaczyk MJM, Waye JS. The Smith-Lemli-Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology. Clin Genet 2001; 59 (06) 375-386
    CrossrefPubMedGoogle Scholar
  • 7 Patrono C, Dionisi-Vici C, Giannotti A. , et al. Two novel mutations of the human delta7-sterol reductase (DHCR7) gene in children with Smith-Lemli-Opitz syndrome. Mol Cell Probes 2002; 16 (04) 315-318
    CrossrefPubMedGoogle Scholar
  • 8 Witsch-Baumgartner M, Ciara E, Löffler J. , et al. Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations. Eur J Hum Genet 2001; 9 (01) 45-50
    CrossrefPubMedGoogle Scholar
  • 9 Jira PE, Wanders RJ, Smeitink JA. , et al. Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith–Lemli–Opitz syndrome. Ann Hum Genet 2001; 65 (Pt 3): 229-236
    CrossrefPubMedGoogle Scholar
  • 10 Waterham HR, Hennekam RC. Mutational spectrum of Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet 2012; 160C (04) 263-284
    CrossrefPubMedGoogle Scholar
  • 11 Prasad C, Marles S, Prasad AN. , et al. Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype. Am J Med Genet 2002; 108 (01) 64-68
    CrossrefPubMedGoogle Scholar
  • 12 Neklason DW, Andrews KM, Kelley RI, Metherall JE. Biochemical variants of Smith-Lemli-Opitz syndrome. Am J Med Genet 1999; 85 (05) 517-523
    CrossrefPubMedGoogle Scholar
  • 13 Battaile KP, Battaile BC, Merkens LS, Maslen CL, Steiner RD. 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 2001; 72 (01) 67-71
    CrossrefPubMedGoogle Scholar
  • 14 Parker CB, Hogue CJ, Koch MA. , et al; Stillbirth Collaborative Research Network. Stillbirth Collaborative Research Network: design, methods and recruitment experience. Paediatr Perinat Epidemiol 2011; 25 (05) 425-435
    CrossrefPubMedGoogle Scholar
  • 15 Stillbirth Collaborative Research Network Writing Group. Association between stillbirth and risk factors known at pregnancy confirmation. JAMA 2011; 306 (22) 2469-2479
    CrossrefPubMedGoogle Scholar
  • 16 Dudley DJ, Goldenberg R, Conway D. , et al; Stillbirth Research Collaborative Network. A new system for determining the causes of stillbirth. Obstet Gynecol 2010; 116 (2 Pt 1): 254-260
    CrossrefPubMedGoogle Scholar
  • 17 Hamilton BE, Martin JA, Osterman MJK, Curtin SC, Mathews TJ. National Vital Statistics Reports: Births: Final Data for 2014. Atlanta, GA: Centers for Disease Control and Prevention; 2015
    Google Scholar
  • 18 MacDorman MF, Gregory ECW. National Vital Statistics Reports: Fetal and Perinatal Mortality: United States, 2013. Atlanta, GA: Centers for Disease Control and Prevention; 2015
    Google Scholar
  • 19 Cross JL, Iben J, Simpson CL. , et al. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. Clin Genet 2015; 87 (06) 570-575
    CrossrefPubMedGoogle Scholar
  • 20 Mills K, Mandel H, Montemagno R, Soothill P, Gershoni-Baruch R, Clayton PT. First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency). Pediatr Res 1996; 39 (05) 816-819
    CrossrefPubMedGoogle Scholar
  • 21 Schoen E, Norem C, O'Keefe J, Krieger R, Walton D, To TT. Maternal serum unconjugated estriol as a predictor for Smith-Lemli-Opitz syndrome and other fetal conditions. Obstet Gynecol 2003; 102 (01) 167-172
    PubMedGoogle Scholar
  • 22 Abuelo DN, Tint GS, Kelley R, Batta AK, Shefer S, Salen G. Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols. Am J Med Genet 1995; 56 (03) 281-285
    CrossrefPubMedGoogle Scholar
  • 23 Linck LM, Hayflick SJ, Lin DS. , et al. Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol Delta(7)-reductase activity in chorionic villi. Prenat Diagn 2000; 20 (03) 238-240
    CrossrefPubMedGoogle Scholar
  • 24 Loeffler J, Utermann G, Witsch-Baumgartner M. Molecular prenatal diagnosis of Smith-Lemli-Opitz syndrome is reliable and efficient. Prenat Diagn 2002; 22 (09) 827-830
    CrossrefPubMedGoogle Scholar
  • 25 Löffler J, Trojovsky A, Casati B, Kroisel PM, Utermann G. Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am J Med Genet 2000; 95 (02) 174-177
    CrossrefPubMedGoogle Scholar