Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population.
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ABSTRACT:
SUBMITTER: Luo X
PROVIDER: S-EPMC8498043 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition. There may be a potential association between genotypes and phenotypes. We investigated the characteristics of LIG4 syndrome in a Chinese cohort. RESULTS:All seven patients had growth restriction. Most patients (6/7) had significant microcephaly (< -?3 SD). Recurrent bacterial infections of the lungs and intestines were the most common symptoms. One patient had myelodysplastic syndromes. One patient presented with an inflammatory bowel disease (IBD)-like phenotype. Patients presented with combined immunodeficiency. The proportions of naïve CD4+ and naïve CD8+ T cells decreased notably in five patients. All patients harbored compound heterozygous mutations in the LIG4 gene, which consisted of a missense mutation (c.833G?>?T, p.R278L) and a deletion shift mutation, primarily c.1271_1275delAAAGA (p.K424Rfs*20). Two other deletion mutations, c.1144_1145delCT and c.1277_1278delAA, were novel. Patients with p.K424Rfs*20/p.R278 may have milder dysmorphism but more significant IgA/IgM deficiency compared to the frequently reported genotype p.R814X/p.K424Rfs*20. One patient underwent umbilical cord blood stem cell transplantation (UCBSCT) but died. CONCLUSIONS:The present study reported the clinical and molecular characteristics of a Chinese cohort with LIG4 syndrome, and the results further expand the phenotypic and genotypic spectrum and our understanding of genotype-to-phenotype correlations in LIG4 syndrome.
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Project description:BACKGROUND: Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RET(R114H)) has recently been identified in approximately 6-7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RET(R114H) in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population. METHODOLOGY AND PRINCIPAL FINDINGS: To test whether all RET(R114) were originated from a single mutational event, we predicted the approximate age of RET(R114H) by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4-23 generations old depending on growth rate. We reasoned that if RET(R114H) was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RET(R114H) patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RET(R114H) that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients. CONCLUSIONS: This suggests that RET(R114H) is a founder mutation for HSCR in the Chinese population.
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Project description:Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide. Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed. Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population. Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.
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Project description:BACKGROUND AND OBJECTIVES:This retrospective study analysed a case series of subjects with citrin deficiency, and aims to present the molecular and clinical characterization of this disease in the Hong Kong Chinese population for the first time. PATIENTS AND METHODS:Data from medical records of eighteen patients with citrin deficiency (years 2006-2015) were retrieved. Demographic data, biochemical parameters, radiological results, genetic testing results, management, and clinical outcome were collected and analysed. RESULTS:Eighteen patients with diagnosis of citrin deficiency were recruited. All 18 patients carried at least one common pathogenic variant c.852_855delTATG in SLC25A13. Prolonged jaundice (neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD) was the most common presenting symptom, in conjunction with elevated plasma citrulline, threonine, alkaline phosphatase, and alpha-fetoprotein levels. The abnormal biochemical parameters including liver derangement returned to normal range in most of the cases by 6?months of age after the introduction of a lactose-free formula. There were a few cases with atypical presentations. Two subjects did not present with NICCD, and were subsequently diagnosed later in life after their siblings presented with symptoms of citrin deficiency at one month of age and subsequently received a molecular diagnosis. One patient with citrin deficiency also exhibited multiple liver hemangioendotheliomas, which subsided gradually after introduction of a lactose-free formula. Only one patient from this cohort was offered expanded metabolic screening at birth. She was not ascertained by conducted newborn screening and was diagnosed upon presentation with cholestatic jaundice by 1?month of age. CONCLUSION:This is the first report of the clinical and molecular characterization of a large cohort of patients with citrin deficiency in Hong Kong. The presentation of this cohort of patients expands the clinical phenotypic spectrum of NICCD. Benign liver tumors such as hemangioendotheliomas may be associated with citrin deficiency in addition to the well-known association with hepatocellular carcinoma. Citrin deficiency may manifest in later infancy period with an NICCD-like phenotype. Furthermore, this condition is not always ascertained by expanded newborn metabolic screening testing.
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