Assessing Postnatal Mortality in Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder caused by pathological variants in DHCR7, resulting in a deficiency in the enzyme 7-dehydrocholesterol reductase. This results in elevated levels of cholesterol precursors and typically low cholesterol levels, leading to a range of physical and cognitive challenges. Mortality rates in infants with severe SLOS are high, due to congenital malformations. Premature death has been described in individuals with SLOS, particularly in severely affected individuals. Further research is needed to understand postnatal mortality risk factors for individuals with SLOS. Understanding these factors could improve monitoring and prevention efforts. To investigate this, we obtained death certificates from the National Death Index (NDI) database on a cohort of individuals with SLOS who were enrolled in natural history studies at the National Institutes of Health Clinical Center (NCT00001721 and NCT05047354). Analysis and comparison of this deceased cohort showed that although premature death occurs in SLOS, many individuals with SLOS survive into adulthood. We also observed the risk of postnatal mortality increasing with higher severity scores and lower initial cholesterol levels. Trial Registration: NCT00001721 and NCT05047354.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.

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.

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.

Human Genetics of Atrial Septal Defect.

Although atrial septal defects (ASD) can be subdivided based on their anatomical location, an essential aspect of human genetics and genetic counseling is distinguishing between isolated and familiar cases without extracardiac features and syndromic cases with the co-occurrence of extracardiac abnormalities, such as developmental delay. Isolated or familial cases tend to show genetic alterations in genes related to important cardiac transcription factors and genes encoding for sarcomeric proteins. By contrast, the spectrum of genes with genetic alterations observed in syndromic cases is diverse. Currently, it points to different pathways and gene networks relevant to the dysregulation of cardiomyogenesis and ASD pathogenesis. Therefore, this chapter reflects the current knowledge and highlights stable associations observed in human genetics studies. It gives an overview of the different types of genetic alterations in these subtypes, including common associations based on genome-wide association studies (GWAS), and it highlights the most frequently observed syndromes associated with ASD pathogenesis.

Human Genetics of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital cardiovascular malformation characterized by hypoplasia of the left ventricle, aorta, and other structures on the left side of the heart. The pathologic definition includes atresia or stenosis of both the aortic and mitral valves. Despite considerable progress in clinical and surgical management of HLHS, mortality and morbidity remain concerns. One barrier to progress in HLHS management is poor understanding of its cause. Several lines of evidence point to genetic origins of HLHS. First, some HLHS cases have been associated with cytogenetic abnormalities (e.g., Turner syndrome). Second, studies of family clustering of HLHS and related cardiovascular malformations have determined HLHS is heritable. Third, genomic regions that encode genes influencing the inheritance of HLHS have been identified. Taken together, these diverse studies provide strong evidence for genetic origins of HLHS and related cardiac phenotypes. However, using simple Mendelian inheritance models, identification of single genetic variants that "cause" HLHS has remained elusive, and in most cases, the genetic cause remains unknown. These results suggest that HLHS inheritance is complex rather than simple. The implication of this conclusion is that researchers must move beyond the expectation that a single disease-causing variant can be found. Utilization of complex models to analyze high-throughput genetic data requires careful consideration of study design.

Traumatic Self-Inflicted Ventricular Laceration: A Case of Smith-Lemli-Opitz Syndrome in an Adult.

Adults with intellectual and developmental disabilities (IDD) are increasingly living into adulthood, highlighting the need for adult clinicians to expand their familiarity with congenital conditions. Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive inborn error of cholesterol synthesis. SLOS is commonly diagnosed in childhood, but a number of adults with IDD progress into adulthood without a formal diagnosis. We present an 18-year-old male with a history of IDD and altered pain sensation who was hospitalized following a self-inflicted knife injury resulting in a traumatic ventricular septal defect. Over the following 15 years, the patient continued to exhibit self-injurious behaviors. At the age of 33, caregivers consented to further work-up of his intellectual disability, and whole-exome genetic sequencing revealed a diagnosis of SLOS. The clinical course of this patient represents a unique presentation of altered pain sensation, a delayed diagnosis of SLOS into adulthood, and the challenges of providing care to an adult with IDD. The case further highlights the importance of understanding the typical workup and management of genetic and congenital conditions arising in childhood.

Cholesterol alterations in fragile X syndrome, autism spectrum disorders and other neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) are a group of etiologically diverse diseases primarily associated with abnormal brain development, impaired cognition, and various behavioral problems. The majority of NDDs present a wide range of clinical phenotypes while sharing distinct cellular and biochemical alterations. Low plasma cholesterol levels have been reported in a subset of NNDs including, autism spectrum disorder (ASD) and fragile X syndrome (FXS). The present review focuses on cholesterol metabolism and discusses the current evidence of lipid disruption in ASD, FXS, and other genetically related NDDs. The characterization of these common deficits might provide valuable insights into their underlying physiopathology and help identify potential therapeutic targets.

MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by genetic mutations in the DHCR7 gene, encoding the enzyme 3ß-hydroxysterol-Δ7-reductase (DHCR7) that catalyzes the last step of cholesterol synthesis. The resulting deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC), have a profound impact on brain development, which manifests as developmental delay, cognitive impairment, and behavioral deficits. To understand how the brain regions are differentially affected by the defective Dhcr7, we aim to map the regional distribution of sterols and other lipids in neonatal brains from a Dhcr7-KO mouse model of SLOS, using mass spectrometry imaging (MSI). MSI enables spatial localization of biomolecules in situ on the surface of a tissue section, which is particularly useful for mapping the changes that occur within a metabolic disorder such as SLOS, and in an anatomically complex organ such as the brain. In this work, using MALDI-ion mobility (IM)-MSI, we successfully determined the regional distribution of features that correspond to cholesterol, 7-DHC/desmosterol, and the precursor of desmosterol, 7-dehydrodesmosterol, in WT and Dhcr7-KO mice. Interestingly, we also observed m/z values that match the major oxysterol metabolites of 7-DHC (DHCEO and hydroxy-7-DHC), which displayed similar patterns as 7-DHC. We then identified brain lipids using m/z and CCS at the Lipid Species-level and curated a database of MALDIIM-MS-derived lipid CCS values. Subsequent statistical analysis of regions-of-interest allowed us to identify differentially expressed lipids between Dhcr7-KO and WT brains, which could contribute to defects in myelination, neurogenesis, neuroinflammation, and learning and memory in SLOS.

Keeping you on your toes: Smith-Lemli-Opitz Syndrome is an easily missed cause of developmental delays.

Smith-Lemli-Opitz syndrome (SLOS) is a relatively common genetic cause of developmental delay and may only present in conjunction with 2,3 toe syndactyly. This case series illustrates a milder phenotype of SLOS, where the predominant findings are neurocognitive in the presence of 2,3 toe syndactyly.

Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk.

Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith-Lemli-Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte-microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte-microglia immune axis, with possible implications in other neurological diseases.

7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome.

Defective 3ß-hydroxysterol-Δ7 -reductase (DHCR7) in the developmental disorder, Smith-Lemli-Opitz syndrome (SLOS), results in a deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC). Here, we show that loss of DHCR7 causes accumulation of 7-DHC-derived oxysterol metabolites, premature neurogenesis from murine or human cortical neural precursors, and depletion of the cortical precursor pool, both in vitro and in vivo. We found that a major oxysterol, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), mediates these effects by initiating crosstalk between glucocorticoid receptor (GR) and neurotrophin receptor kinase TrkB. Either loss of DHCR7 or direct exposure to DHCEO causes hyperactivation of GR and TrkB and their downstream MEK-ERK-C/EBP signaling pathway in cortical neural precursors. Moreover, direct inhibition of GR activation with an antagonist or inhibition of DHCEO accumulation with antioxidants rescues the premature neurogenesis phenotype caused by the loss of DHCR7. These results suggest that GR could be a new therapeutic target against the neurological defects observed in SLOS.

How to Manage Low Estriol Levels in Pregnancies, One Center Experience.

Objective: Low estriol (uE3) levels in the second-trimester screening for Down syndrome may be the result of fetal demise, congenital abnormalities, or some genetic hormonal disorders of the fetus. Although X-linked ichthyosis, a microdeletion syndrome with mild ichthyosis, which causes steroid sulfatase (STS) deficiency, is the most common genetic cause, second-trimester screening tests calculate the risk for a less common and severe disorder known as the Smith Lemli Opitz syndrome (SLOS). We aimed to investigate the outcomes of pregnancies with low uE3 levels in Down syndrome screening and emphasize the high prevalence of STS deficiency instead of SLOS in such cases. Methods: Fifteen pregnancies with very low uE3 levels and high risk for trisomy and/or SLOS in screening tests were evaluated and tested for STS deficiency and SLOS. Results: Seven of the pregnancies had STS microdeletion syndrome, while additional two cases were supposed to have STS gene mutation according to family and/or postnatal history. Although one fetal death was recorded, no chromosomal abnormality, SLOS, or congenital malformation was recorded in our series. Conclusions: SLOS is a very severe and rare syndrome. The risk estimation for SLOS in screening tests causes stress for pregnant women and healthcare givers. We recommend the addition of risk estimation for STS deficiency when a low uE3 level is detected in the screening test.

Isolated autism is not an indication for Smith-Lemli-Opitz syndrome biochemical testing.

Several studies have demonstrated a high incidence of autistic spectrum features in individuals with Smith-Lemli-Opitz syndrome (SLOS). However, do these findings imply a converse relationship that has diagnostic utility? Is SLOS testing implicated when autism spectrum disorder (ASD) is the only clinical indication? AIM: To determine if there is any correlation with a clinical indication of ASD and a biochemical diagnosis of SLOS, based on historical test request and assay data. METHODS: Six years (2008-2013) of clinical test requests for 7-dehydrocholesterol (7-DHC) level were classified and summarised according to indication and final test result. RESULTS: From the audit period, 988 valid test results from post-natal samples were identified. In plasma/serum, mean 7-DHC level was 264.7 µmol/L (normal range < 2.0) for confirmed SLOS cases. No tests performed due to an isolated clinical indication of ASD or where no clinical information was supplied were associated with 7-DHC levels diagnostic for SLOS. CONCLUSIONS: Historical test data analysis supports the recommendation that autism/ASD as a single clinical feature is not an appropriate indication for SLOS (7-DHC) biochemical testing.

A reliable tool for detecting 7-dehydrocholesterol and cholesterol in human plasma and its use in diagnosis of Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome is a birth defect caused by the deficiency of 7-dehydrocholesterol reductase in cholesterol biosynthesis pathway, which leads to accumulation of 7-dehydrocholesterol and reduction of cholesterol in body fluids. To effectively diagnose Smith-Lemli-Opitz syndrome and monitor therapy, a reliable method for simultaneous detection of 7-dehydrocholesterol and cholesterol is needed. METHODS: In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), 50 µL of human plasma were hydrolyzed at 70℃ for 40 min with 1 M potassium hydroxide in 90% ethanol, and then 7-dehydrocholesterol and cholesterol were extracted by 600 µL of n-hexane for three times. After microwave-assisted derivatization with 70 µL of N,O-bis(trimethylsilyl)trifluoroacetamide at 460 W for 3 min, the analytes were measured by gas chromatography-mass spectrometry. RESULTS: The limits of detection were 100 ng/mL for 7-dehydrocholesterol and 300 ng/mL for cholesterol. Good linearity was obtained in the range of 1-600 µg/mL for 7-dehydrocholesterol and 10-600 µg/mL for cholesterol, which completely covered the biochemical levels of Smith-Lemli-Opitz syndrome patients that have been reported. CONCLUSION: A time-saving and accurate gas chromatography with mass spectrometry based method was developed for the determination of 7-dehydrocholesterol and cholesterol in human plasma, which also serves as a useful tool for Smith-Lemli-Opitz syndrome diagnosis, treatment, and research.

Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis.

Clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis in mammalian cells. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of human disorders of cholesterol metabolism. We report that inhibition of post-squalene cholesterol biosynthesis impairs CME. Imaging of membrane bending dynamics and the CME pit ultrastructure reveals prolonged clathrin pit lifetimes and shallow clathrin-coated structures, suggesting progressive impairment of curvature generation correlates with diminishing sterol abundance. Sterol structural requirements for efficient CME include 3' polar head group and B-ring conformation, resembling the sterol structural prerequisites for tight lipid packing and polarity. Furthermore, Smith-Lemli-Opitz fibroblasts with low cholesterol abundance exhibit deficits in CME-mediated transferrin internalization. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest that reduced CME activity may contribute to cellular phenotypes observed within disorders of cholesterol metabolism.

Smith-Lemli-Opitz Syndrome: Bosnian and Herzegovinian Experience.

The aim of this paper is to present a patient with the Smith-Lemli-Opitz syndrome (SLOS), with an overview of the modality of diagnosis, and the treatment of the patient. Exome analysis showed two variants in exon 6 of the 7-dehydrocholesterol reductase (DHCR7) gene have been determined: missense variant 1) NM_001360.2: c.470T>C (p.Leu157Pro) and 2) nonsense variant c.452G>A (W151*). Therefore the DHCR7 genotype of the patient is NM_001360.2: c.[470T>C; c.452G>A]. The proband, aged 6 years, has global developmental retardation with missing contact gaze and lacking motor development for her age and with peripheral spastic-enhanced muscle tone, and is under the supervision of children neurologists, gastroenterologists, nephrologists and cardiologists.

Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients.

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 µmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 µmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.

A Case of Smith-Lemli-Opitz Syndrome Diagnosed with Hypertrophic Pyloric Stenosis.

Smith-Lemli-Opitz syndrome (SLOS) is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase (DHCR7) that results in an abnormality in cholesterol metabolism. SLOS is inherited as an autosomal recessive genetic disorder. In this case, we describe a 34-day-old patient with postnatal progressive projectile vomiting, diagnosed with hypertrophic pyloric stenosis, who was suspected to have SLOS during treatment clinical and biochemical profile. A 34-day-old patient with progressively worsening vomiting and abdominal distention, diagnosed as hypertrophic pyloric stenosis, was operated by pediatric surgery department. After operation, the patient required pediatric intensive care unit admission due to respiratory distress, anemia, hypoalbuminemia, and generalized edema. Physical examination of our patient revealed dysmorphic facial features, finger anomalies, sacral dimple, and ambiguous genitalia, with chromosomal determination as XY. Molecular genetic testing was performed, and mutations in the DHCR7 gene of homozygous c.1342G>A/p.Glu448Lys (rs80338864) were detected. Infants with progressive projectile vomiting, feeding problems, and multiple anomalies with dysmorphic facial anomalies may be suspected to have SLOS and their families should be advised to have genetic testing and genetic counseling.

Cerebrotendinous xanthomatosis, sitosterolemia, Smith-Lemli-Opitz syndrome and the seminal contributions of Gerald Salen, MD (1935-2020).

Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma ß-sitosterol. These patients have a defect causing overabsorption of ß-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world.

Carrier frequency and incidence estimation of Smith-Lemli-Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2-3 syndactyly of the toes. SLOS is caused by defective 7-dehydrocholesterol reductase, which is encoded by the DHCR7 gene. This study aimed to analyze the carrier frequency and expected incidence of SLOS in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) through the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline (2015 ACMG-AMP guideline). METHODS: We analyzed 9197 exomes for East Asian populations from gnomAD, comprising 1909 Korean, 76 Japanese, and 7212 other East Asian populations. All identified variants were classified according to the 2015 ACMG-AMP guideline. RESULTS: According to the 2015 ACMG-AMP guideline, 15 pathogenic variant/likely pathogenic variant (PV/LPV) cases were identified in 33 East Asian individuals (33/9191 = 0.4%). Among them, four PVs/LPVs were identified in 19 Korean individuals (19/1909 = 1.0%). The predicted incidence, based upon the carrier rates of PV/LPV of DHCR7 alleles, is 1 in 310,688 in East Asians and l in 40,380 in Koreans. CONCLUSIONS: This study is the first to identify carrier frequencies in East Asians and Koreans using gnomAD. It was confirmed that East Asians (0.4%) had a lower carrier frequency than did other ethnicities (1-3%) and Koreans (1.0%) had similar or lower carrier frequencies than other ethnicities. The variant spectrums of DHCR7 in East Asian and Korean populations differed greatly from those of other ethnic groups.