High frequency of p.Thr93Met in Smith‐Lemli‐Opitz syndrome patients in Turkey

Kalb, Stefanie; Çağlayan, Ahmet Okay; Değerli̇yurt, Aydan; Schmid, Stefan; Ceylaner, Serdar; HATİPOĞLU>, Nihal; Hinderhofer, Katrin; Rehder, Helga; Kurtoğlu, Selim; Ceylaner, Gülay; Zschocke, Johannes; Witsch‐Baumgartner, Martina

doi:10.1111/j.1399-0004.2011.01750.x

Cited by 3 publications

(5 citation statements)

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“…Their parents had two pregnancies, which resulted in still births 17 . All reported mild cases had nonfamilial 2–3 toe syndactyly with more than half having subtle facial appearance (ptosis, short‐upturned nose, microcephaly), feeding issues, poor weight gain, developmental delay, and behavioral issues 15‐18 . All cases had an elevated 7‐DHC although sometimes only slightly increased and all had normal cholesterol 15‐17 .…”

Section: Discussionmentioning

confidence: 99%

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

2020

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Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder caused by variants in the DHCR7 gene. In cholesterol biosynthesis, 7‐dehydrocholesterol (7‐DHC) is converted to cholesterol by the enzyme 7‐DHC reductase, which is encoded by the gene DHCR7. Thus, an elevated 7‐DHC is indicative of SLOS. Characteristically SLOS is usually associated with congenital anomalies, dysmorphisms, and moderate to severe neurodevelopmental delay. However, there are rare descriptions of individuals with milder phenotypes. We report a mild case of SLOS presenting with short stature, cleft palate, imperforate anus, and mild language delay with subtle dysmorphic features. 7‐DHC was not elevated at 1 year of age and SLOS considered excluded at this time. The parents had two pregnancies with holoprosencephaly. Whole exome sequencing of one of the fetuses identified compound heterozygous pathogenic variants in the DHCR7 gene (c.964‐1G>C (p.?) and c.1039G>A (p.Gly347Ser) causative of SLOS. The proband with a mild form of SLOS was also found to have the same DHCR7 variants as the fetus and repeat testing of 7‐DHC at 4 years of age was elevated, in keeping with SLOS. This case is the first to describe a wide intrafamilial phenotypic spectrum of SLOS as a result of the same DHCR7 genotype. This case also supports the findings of others that a normal or near normal development should not exclude SLOS. As demonstrated in this case exclusion of a metabolic diagnosis because of a negative biochemical marker such as 7‐DHC is not absolute and if clinical suspicion remains genomic sequencing is warranted.

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Section: Discussionmentioning

confidence: 99%

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

2020

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“…In addition to our patient and the cases reported in the aforementioned studies, a literature review revealed 2 patients from Germany and 1 patient from Slovakia with the p.Tyr432Cys variant [17,18]. A total of 9 patients with this variant (p.Tyr432Cys) were reported in the literature so far [11,[15][16][17][18]. The clinical and genotypic findings for all cases with this variation are summarized in Table 1.…”

Section: Discussionmentioning

confidence: 57%

“…There were compound heterozygous p.Trp151*/p.Tyr432Cys (0/TM) variations in the other patient, and the clinical severity was reported as moderate [15]. A Turkish cohort study reported the variation in the present patient (p.Tyr432Cys) as a compound heterozygous (p.V273G/p.Tyr432Cys -TM/TM) in 1 patient Smith-Lemli-Opitz Syndrome in a 73-Year-Old Woman [16]. Nevertheless, the aforementioned study did not include detailed data on the clinical status of the patient with compound heterozygosity for this variation.…”

Section: Discussionmentioning

confidence: 99%

“…The homozygous p.Thr93Met variation was detected in the first genetically confirmed case reported from Turkey [20]. In 2012, Kalb et al [16] reported that p.Thr93Met was the most prevalent variation (36%) in 14 patients with SLOS from Turkey. A review of the data from recent studies suggested that the p.Tyr432Cys variation found in our patient may be a more prevalent genetic variation for Turkish, German, and Hungarian populations.…”

Section: Discussionmentioning

confidence: 99%

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Smith-Lemli-Opitz Syndrome with Biallelic c.1295A>G (p.Tyr432Cys) Variant in the DHCR7 Gene in a 73-Year-Old Woman: Report of the Oldest Patient

Yılmaz,

Bebek,

Turkyilmaz

2024

Mol Syndromol

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Introduction: Smith-Lemli-Opitz syndrome (SLOS), a genetic developmental disorder characterized by various congenital anomalies, arises from a loss of normal DHCR7 enzymatic action in cholesterol biosynthesis. This syndrome is typically marked by various congenital anomalies, including microcephaly with cognitive impairments, distinctive facial features, and syndactyly of the toes (2-3 fusion). Case Presentation: A 73-year-old woman, followed up on by the neurology clinic for the last 3 years for amnesia and movement disorders, was referred to our clinic for genetic etiology investigation. Although there were no significant dysmorphic findings on her physical examination, observations included partial syndactyly between the second and third toes of both feet, a wide forehead, and a triangular face. We used the whole-exome sequencing (WES) analysis to evaluate the patient because of their various phenotype, which included dysmorphic features, movement problems, recurrent hip dislocation, mild intellectual impairment. WES analysis revealed a homozygous missense c.1295A>G (p.Tyr432Cys) variation in DHCR7 gene. Discussion: A total of 9 patients with p.Tyr432Cys variant have been reported in the literature so far. The present case is the first patient with biallelic c.1295A>G (p.Tyr432Cys) variation in DHCR7 gene in the current literature. Diagnosing the disorder can be challenging, particularly in its milder manifestations, given the extensive range of clinical presentations. The present case is the oldest patient with SLOS reported in the relevant literature. Mild dysmorphic features, mild intellectual disability, and recurrent hip dislocation, along with the typical finding of syndactyly between the second and third toes in the foot, may indicate mild forms of SLOS.

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“…15 While the variant detected in the proband was novel, there have been other missense variants reported at the same position and with the same resulting amino acid change described in patients with SLOS. 16,17 However, SLOS is an autosomal-recessive condition and no second variant of interest was detected in this gene, nor was there evidence of copy number variation within this region of the genome. It is, however, possible to speculate that while multi-organ developmental abnormalities classical of SLOS are caused by biallelic mutations in DHCR7 , heterozygous missense mutations in the same gene may be responsible for nonsyndromic congenital anomalies of the kidney and urinary tract.…”

Section: Resultsmentioning

confidence: 99%

Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

et al. 2017

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Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype-genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death.

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High frequency of p.Thr93Met in Smith‐Lemli‐Opitz syndrome patients in Turkey

Cited by 3 publications

References 15 publications

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

Smith-Lemli-Opitz Syndrome with Biallelic c.1295A>G (p.Tyr432Cys) Variant in the <i>DHCR7</i> Gene in a 73-Year-Old Woman: Report of the Oldest Patient

Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

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High frequency of p.Thr93Met in Smith‐Lemli‐Opitz syndrome patients in Turkey

Cited by 3 publications

References 15 publications

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

Familial DHCR7 genotype presenting as a very mild form of Smith‐Lemli‐Opitz syndrome and lethal holoprosencephaly

Smith-Lemli-Opitz Syndrome with Biallelic c.1295A&gt;G (p.Tyr432Cys) Variant in the <i>DHCR7</i> Gene in a 73-Year-Old Woman: Report of the Oldest Patient

Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

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Smith-Lemli-Opitz Syndrome with Biallelic c.1295A>G (p.Tyr432Cys) Variant in the <i>DHCR7</i> Gene in a 73-Year-Old Woman: Report of the Oldest Patient