Characterization of large deletions in the <i><scp>DHCR7</scp></i> gene

Lanthaler, Barbara; Hinderhofer, Katrin; Maas, Bianca; Haas, Dorothea; Sawyer, Hilary; Burton-Jones, S.; Carter, K; Suri, Mohnish; Witsch‐Baumgartner, Martina

doi:10.1111/cge.12454

Cited by 9 publications

(6 citation statements)

References 19 publications

(24 reference statements)

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“…Patients diagnosed with SLOS have reduced serum cholesterol which results in multiple congenital defects including intellectual disability, facial dysmorphism, and organ and limb anomalies [43]. SLOS is the result of a mutations in a gene, whose function is limited to cholesterol synthesis and to date has not been associated with defects in isoprenoid synthesis [44]. Thus, we hypothesized that the facial deficits present in animals harboring mutations in hmgcs1 were a consequence of defects in cholesterol synthesis and independent of isoprenoid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

2017

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There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh) signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf), but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.

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Section: Discussionmentioning

confidence: 99%

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

2017

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“…This methodology encompasses the 13 mutations identified by genotyping and other mutations previously known or undescribed. Large deletions and insertions, which may account for 4–5% of causative alleles, would typically not be identified by this methodology. Identified variants were classified for pathogenicity based on the American College of Medical Genetics and Genomics' recommendations for interpretation and reporting using the approach described by Karimi et al .…”

Section: Methodsmentioning

confidence: 99%

Smith–Lemli–Opitz syndrome carrier frequency and estimates of in utero mortality rates

Lazarin¹,

Haque²,

Evans³

et al. 2017

Prenatal Diagnosis

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ObjectiveTo tabulate individual allele frequencies and total carrier frequency for Smith–Lemli–Opitz syndrome (SLOS) and compare expected versus observed birth incidences.MethodsA total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival.ResultsSmith–Lemli–Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise.ConclusionSmith–Lemli–Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

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“…This methodology encompasses the 13 mutations identified by genotyping, the additional four included in the original study, and other mutations previously known or undescribed. Large deletions and insertions, which may account for 4-5% of causative alleles (9,17), would typically not be identified from this methodology. Identified variants were classified for pathogenicity based on the American College of Medical Genetics and Genomics' recommendations for interpretation and reporting using the approach described by Karimi, et al (18).…”

Section: Methodsmentioning

confidence: 99%

Smith-Lemli-Opitz syndrome carrier frequency and estimates ofin uteromortality rates

Lazarin¹,

Haque²,

Evans³

et al. 2016

Preprint

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Capsule (30 words or less):Population screening discovers a carrier frequency similar to that of other commonly tested disorders and suggests a high fetal mortality rate. Title: Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates ABSTRACTObjective: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences.Design: Retrospective analysis of patients from the general population who have undergone carrier screening for SLOS.Setting: Individuals were offered and elected carrier screening in their respective physician's offices.Patients: 262,399 individuals with no indication of family or personal history of Smith-Lemli-Opitz syndrome, primarily US-based, screened for Smith-Lemli-Opitz syndrome mutations as part of an expanded carrier screening panel.Intervention (s): Data on mutations in the DHCR7 gene causing SLOS were analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature are then compared to our data to estimate the effect of SLOS on fetal survival. Main Outcome Measure(s): Individual and cumulative allele frequencies stratified by self-reported patient ethnicity.Results: SLOS carrier frequency is highest in individuals of Ashkenazi Jewish ancestry (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence to that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience fetal demise.Conclusion: SLOS is relatively frequent in certain populations and, due to its impact on fetal survival, merits preconception screening.

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Characterization of large deletions in the DHCR7 gene

Cited by 9 publications

References 19 publications

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

Smith–Lemli–Opitz syndrome carrier frequency and estimates of in utero mortality rates

Smith-Lemli-Opitz syndrome carrier frequency and estimates ofin uteromortality rates

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