OBJECTIVE: To elucidate the epidemiological characteristics and genetic variant profile of Short-chain acyl-CoA dehydrogenase deficiency (SCADD) among newborns from Hainan Province and evaluate its significance within the local neonatal disease screening panel. METHODS: A total of 84 184 newborns born in Hainan Province from February to December 2024 were included. Tandem mass spectrometry (MS/MS) was employed to detect butyrylcarnitine (C4) and propionylcarnitine (C3) levels in dried blood spots. Screening thresholds were set at C4 > 0.43 μ mol/L and C4/C3 ratio > 0.28. Suspected cases underwent confirmatory testing via urinary ethylmalonic acid analysis by gas chromatography-mass spectrometry and whole-exome sequencing for ACADS gene variants. This study was approved by the Medial Ethics Committee of the hospital (Ethics No.: HNWCMC-2024-55). RESULTS: Six SCADD cases (male-to-female ratio = 1:1) were diagnosed, with all carrying compound heterozygous variants at two loci, yielding a prevalence of 7.13 per 100,000 live births. Four known ACADS gene variants were identified, with both c.322G>A and c.625G>A detected at a frequency of 41.7%. Regular follow-up (as of January 2026) revealed that all diagnosed cases have remained asymptomatic with normal growth and development. CONCLUSION The prevalence of SCADD among newborns in Hainan Province is relatively high, with c.322G>A and c.625G>A as the hotspot variants in the region. Given the absence of clinical phenotypes in all screen-detected cases during long-term follow-up, it is recommended to remove this condition from the routine neonatal screening program for this region to reduce unnecessary anxiety and medical cost.
Humans ; Infant, Newborn ; Neonatal Screening/methods* ; Female ; Male ; Lipid Metabolism, Inborn Errors/epidemiology* ; Acyl-CoA Dehydrogenase/genetics* ; China/epidemiology* ; Follow-Up Studies

OBJECTIVE: To explore the genetic basis of a child with Chanarin-Dorfman syndrome (CDS) manifesting as ichthyosis. METHODS: A child who had presented at Henan Provincial People's Hospital in June 2023 was selected as study subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing. Relevant literature was searched in databases using key words "Chanarin-Dorfman syndrome" and "ABHD5 gene". The clinical manifestations and variant sites of previously reported cases were compiled and analyzed for correlations. This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital [Ethics No.: (2019) Jun Shen No. (134)]. RESULTS: WES revealed that the child has harbored compound heterozygous variants of the ABHD5 gene, namely c.99_103del (p.H34*) in exon 2 and c.770C>G (p.P257R) in exon 5, which were inherited from her father and mother, respectively. Bioinformatic analysis suggested that both variants were pathogenic. Literature review indicated that the affected organs in CDS are ranked from most to least including liver, eyes, ears, nervous system, muscles, spleen, and kidneys. The c.594insC and c.594dupC variants are most common. CONCLUSION The identification of the two novel ABHD5 gene variants has enriched the mutation spectrum of CDS. c.594insC or c.594dupC are hotspot mutations of this disease, albeit with no definitive correlation between the genotype and phenotype.
Humans ; Female ; Ichthyosiform Erythroderma, Congenital/genetics* ; Lipid Metabolism, Inborn Errors/genetics* ; Phenotype ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics* ; Mutation ; Muscular Diseases/genetics* ; Exome Sequencing ; Child ; Male ; Child, Preschool

OBJECTIVE: To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. METHODS: Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). RESULTS: Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871_1873del(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NM_000527.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936_6937inv (p.Ile2313Val) in the APOB gene (NM_000384). According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871_1873del (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936_6937inv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). CONCLUSION Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents.
Humans ; Hyperlipoproteinemia Type II/drug therapy* ; Male ; Female ; Heterozygote ; Adult ; Middle Aged ; Receptors, LDL/genetics* ; Retrospective Studies ; Mutation ; Exome Sequencing

OBJECTIVE: To report and analyze a case of Juvenile neuronal ceroid lipofuscinosis (NCL) due to compound heterozygous variants of PPT1 gene. METHODS: A child who was admitted to the Department of Neurology of West China Hospital of Sichuan University in April 2021 due to "intellectual decline and behavioral abnormalities for more than 5 years and movement disorder for more than 1 year" was selected as the study subject. Clinical data of the child was collected. Trio-whole exome sequencing was carried out for the child and his parents, and clinical follow-up was conducted. This study has been approved by the Medical Ethics Committee of West China Hospital of Sichuan University (Ethic No. 2024-2286). RESULTS: The patient, a 13-year-old male, showed progressive mental decline, behavioral abnormalities, and movement disorders from the age of 8. Electroencephalogram showed abnormal background activities, and magnetic resonance imaging showed brain atrophy. Trio-whole exome sequencing revealed that he had harbored a paternally derived heterozygous c.272(exon3)A>C variant and a maternally derived heterozygous c.176(exon2)A>G variant of the PPT1 gene. His presentation was in keeping with previously reported juvenile NCL due to variants of the PPT1 gene. CONCLUSION The c.272(exon3)A>C and c.176(exon2)A>G compound heterozygous variants of the PPT1 gene probably underlay the Juvenile NCL in this child. Discovery of the c.176(exon2)A>G variant has expanded the mutational spectrum of this disease.
Humans ; Neuronal Ceroid-Lipofuscinoses/genetics* ; Male ; Adolescent ; Heterozygote ; Thiolester Hydrolases/genetics* ; Membrane Proteins/genetics* ; Exome Sequencing ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic variants in a patient with adult ceroid lipofuscinosis neuronal type 7 (ACLN7). METHODS: A female patient diagnosed with ACLN7 in Henan Provincial People's Hospital in June 2021 was selected as the study subject. Clinical data, auxiliary examination and result of genetic testing were retrospectively analyzed. RESULTS: The patient, a 39-year-old female, has mainly presented progressive visual loss, epilepsy, cerebellar ataxia and mild cognitive decline. Neuroimaging analysis has revealed generalized brain atrophy, prominently cerebellum. Fundus photography has revealed retinitis pigmentosa. Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells. Whole exome sequencing revealed that she has harbored compound heterozygous variants of the MSFD8 gene, namely c.1444C>T (p.R482*) and c.104G>A (p.R35Q). Among these, c.1444C>T (p.R482*) was a well established pathogenic variant, while c.104G>A (p.R35Q) was a missense variant unreported previously. Sanger sequencing confirmed that the daughter, son and elder brother of the proband have respectively carried heterozygous c.1444C>T (p.R482*), c.104G>A (p.R35Q), and c.104G>A (p.R35Q) variants of the same gene. The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7. CONCLUSION Compared with previously reported cases, this patient has the latest onset of the disease with a non-lethal phenotype. Her clinical features have involved multiple systems. Cerebellar atrophy and fundus photography may be indicative of the diagnosis. The c.1444C>T (p.R482*) and c.104G>A (p.R35Q) compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.
Male ; Female ; Humans ; Membrane Transport Proteins/genetics* ; Neuronal Ceroid-Lipofuscinoses/diagnosis* ; Retrospective Studies ; Atrophy ; Mutation

OBJECTIVE: To analyze variant of LDLR gene in a patient with familial hypercholesterolemia (FH) in order to provide a basis for the clinical diagnosis and genetic counseling. METHODS: A patient who had visited the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University in June 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was applied to the patient. Candidate variant was verified by Sanger sequencing. Conservation of the variant site was analyzed by searching the UCSC database. RESULTS: The total cholesterol level of the patient was increased, especially low density lipoprotein cholesterol. A heterozygous c.2344A>T (p.Lys782*) variant was detected in the LDLR gene. Sanger sequencing confirmed that the variant was inherited from the father. CONCLUSION The heterozygous c.2344A>T (p.Lys782*) variant of the LDLR gene probably underlay the FH in this patient. Above finding has provided a basis for genetic counseling and prenatal diagnosis for this family.
Humans ; Cholesterol, LDL/genetics* ; Heterozygote ; Hyperlipoproteinemia Type II/genetics* ; Mutation ; Pedigree ; Phenotype ; Receptors, LDL/genetics*

OBJECTIVE: To explore the clinical and genetic characteristics of four patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). METHODS: Four children who had presented at the Children's Hospital Affiliated to Zhengzhou University between August 2019 and August 2021 were selected as the study subjects. Clinical data of the children were collected. The children were subjected to whole exome sequencing (WES). RESULTS: All of the four children were diagnosed with MCADD. Blood amino acid and ester acyl carnitine spectrum test showed that the concentration of octanoyl carnitine (C8) was significantly increased. The main clinical manifestations included poor mental response (3 cases), intermittent diarrhea with abdominal pain (1 case), vomiting (1 case), increased transaminase (3 cases), and metabolic acidosis (2 cases). Five variants were identified by genetic testing, among which c.341A>G (p.Y114C) was unreported previously. Three were missense variants, one was frameshift variant and one was splicing variant. CONCLUSION The clinical heterogeneity of MCADD is obvious, and the severity of the disease may vary. WES can assist with the diagnosis. Delineation of the clinical symptoms and genetic characteristics of the disease can facilitate early diagnosis and treatment of the disease.
Child ; Humans ; Acyl-CoA Dehydrogenase/genetics* ; Carnitine ; Genetic Testing ; Lipid Metabolism, Inborn Errors/genetics* ; Neonatal Screening

Objective: To identify and analyze 3D architecture of the mutational sites of susceptible genes in a pedigree with familial hypercholesterolemia-like phenotype (FHLP). Methods: This is a case series study. A pedigree with suspected familial hypercholesterolemia was surveyed. The proband admitted in Beijing Anzhen Hospital in April 2019. Whole-exome sequencing was performed to determine the mutational sites of susceptible genes in the proband. Polymerase chain reaction (PCR) sequencing was used to verify the pathogenic variant on proband's relatives. The structural and functional changes of the proteins were analyzed and predicted by Discovery Studio 4.0 and PyMol 2.0. Results: The patients in the pedigree showed abnormal lipid profiles, especially elevated levels of total cholesterol(TC). The genetic screening detected the c.1330C>T SNP in the exon 8 of lipase C (LIPC) gene, this mutation leads to an amino acid substitution from arginine to cysteine at position 444 (Arg444Cys), in the proband and proband's father and brother. In this family, members with this mutation exhibited elevated TC, whereas lipid profile was normal from the proband's mother without this mutation. This finding indicated that LIPC: c.1330C>T mutation might be the mutational sites of susceptible genes. The analysis showed that Arg444Cys predominantly affected the ligand-binding property of the protein, but had a limited impact on catalytic function. Conclusion: LIPC: c.1330C>T is a new mutational site of susceptible genes in this FHLP pedigree.
Humans ; Male ; Hyperlipoproteinemia Type II/genetics* ; Lipase/genetics* ; Lipids ; Mutation ; Pedigree ; Phenotype ; Proteins

Objective: To investigate the impact of orthotopic liver transplantation on serum lipid and growing development in patients with homozygous (HoFH) or compound heterozygotes (cHeFH) familial hypercholesterolemia. Methods: Patients who were treated in Peking Union Medical College Hospital from August 2019 to August 2021, entered the rare disease database and underwent liver transplantation, were included in this single center retrospective cohort study. The height for age Z score (HAZ) and length for age Z score (WAZ) at birth, at the time of transplantation and one year after transplantation were calculated respectively by collecting demographic characteristics, clinical manifestations, echocardiography, lipid-lowering treatment, blood lipid level data and donor characteristics data of liver transplantation. The serum cholesterol level and growing development changes before and after liver transplantation were evaluated. Results: A total of five patients with HoFH or cHeFH, including two females, were included in this study. The median age was 10 years (6-22 years). The median follow up duration was 28 months (24-33 months). All HoFH or cHeFH patients in this study received the maximum daily dosage of the lipid-lowering drug combined with low salt and low-fat diet control treatment for at least 3 months before orthotopic liver transplantation. The average level of total cholesterol (TC) decreased by 27% compared with that before treatment, the level of low-density lipoprotein cholesterol (LDL-C) decreased by 21% after 3 months treatment. There was no intervention of lipid-lowering therapy after operation. One month after liver transplantation, the average levels of TC and LDL-C further decreased rapidly by 68% and 76% respectively. One year after liver transplantation, the level of LDL-C decreased from (17.1±1.6)mmol/L without any intervention before transplantation to (3.0±0.7)mmol/L, and remained stable thereafter. In addition, compared with no intervention before liver transplantation, the serum triglyceride (TG) level decreased after the maximum daily dosage of the lipid-lowering drug and low salt and low-fat diet control for 3 months ((1.88±0.27) mmol/L vs. (1.12±0.55)mmol/L, <i>Pi>=0.031), and the HDL-C level also decreased significantly ((1.95±0.49)mmol/L vs. (0.95±0.30)mmol/L, <i>Pi>=0.006) at the same time period. TG and HDL-C remained stable after liver transplantation during the 24-month follow-up period (<i>Pi>>0.05). One and two years after liver transplantation, there was no significant difference in height and weight, malnutrition and growth retardation between the patients in this cohort and Chinese children of the same age. Conclusion: Early liver transplantation is a feasible and effective treatment option for HoFH or cHeFH patients with extremely high serum low-density lipoprotein cholesterol levels.
Child ; Infant, Newborn ; Female ; Humans ; Cholesterol, LDL/therapeutic use* ; Liver Transplantation ; Homozygous Familial Hypercholesterolemia ; Retrospective Studies ; Hyperlipoproteinemia Type II/surgery* ; Lipids ; Hypolipidemic Agents/therapeutic use*

Humans ; Female ; Coronary Artery Disease/complications* ; Hyperlipoproteinemia Type II/complications* ; Aortic Valve Stenosis/etiology* ; Treatment Outcome