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Background: Ellis-van Creveld syndrome (EVC), a very rare genetic skeletal dysplasia, is clinically characterized by a tetrad consisting of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. The aim of this study was to identify the genetic defect for EVC in a five-generation consanguineous Han-Chinese pedigree., Methods: A five-generation, 12-member Han-Chinese pedigree was enrolled in this study. Exome sequencing was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members and 200 unrelated ethnicity-matched controls., Results: A novel homozygous variant, c.2014C>T, p.(Q672*), in the EvC ciliary complex subunit 1 gene (EVC), was detected in the patient, which was cosegregated with the disease in the family and absent in the controls., Conclusion: The identified novel homozygous EVC variant, c.2014C>T, p.(Q672*), was responsible for EVC in this Han-Chinese pedigree. The findings in this study extend the EVC mutation spectrum and may provide new insights into EVC causation and diagnosis with implications for genetic counseling and clinical management., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Significance: Retinitis pigmentosa (RP) is a severe hereditary retinal disorder characterized by progressive degeneration of rod and cone photoreceptors. This study identified a novel frameshift mutation, c.385delC, p.(L129WfsTer148), in the cyclic nucleotide-gated channel beta 1 (CNGB1) gene of a consanguineous Han Chinese family with autosomal recessive RP (arRP). This expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling., Purpose: The present study sought to identify potential pathogenetic gene mutations in a five-generation consanguineous Han Chinese family with RP., Methods: Two members of a five-generation consanguineous Han Chinese pedigree with arRP and 100 normal individuals were enrolled in this study. Exome sequencing was performed on the 70-year-old male proband from a consanguineous family to screen potential pathogenic mutations according to the American College of Medical Genetics and Genomics for the interpretation of sequence variants. Sanger sequencing was performed on the proband, the proband's unaffected son, and 100 normal individuals to verify the disease-causing mutation., Results: A novel frameshift mutation, c.385delC, p.(L129WfsTer148), with homozygous status in the CNGB1 gene was identified in the proband of the family with arRP, and the mutation with heterozygous status was carried by the asymptomatic son., Conclusions: The c.385delC (p.(L129WfsTer148)) mutation in the CNGB1 gene screened by exome sequencing is probably responsible for the RP phenotype in this family. The result expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling.

Aims: Essential tremor (ET) is one of the most common adult-onset movement disorders. ET and Parkinson's disease (PD) overlap clinically and pathologically, which prompted this investigation into the association of PD risk variants in ET patients. This study was designed to explore the role of variants of two PD-related genes LRRK1 and LRRK2 in a Han Chinese ET population., Materials and Methods: Genetic analysis of LRRK1, rs2924835, and LRRK2, rs34594498, rs34410987, and rs33949390 variants was conducted on 200 Han Chinese patients with ET and 434 ethnically matched normal controls., Results: No statistically significant differences were identified in either genotypic or allelic frequencies of variants between the ET patients and the control cohort (all p > 0.05). Haplotype analysis of three LRRK2 variants (rs34594498, rs34410987, and rs33949390) showed no haplotypes displayed an association with ET risk (all p > 0.05)., Conclusions: The data suggest that LRRK1 variant (rs2924835) and LRRK2 variants (rs34594498, rs34410987, and rs33949390) are not associated with ET in this Han Chinese population.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690-0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD.

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular histological lesion associated with high-grade proteinuria and end-stage renal disease. Histologically, FSGS is characterized by focal segmental sclerosis with foot process effacement. The aim of this study was to identify the disease-causing mutation in a four-generation Chinese family with FSGS. A novel missense mutation, c.1856G>A (p.Gly619Asp), in the collagen type IV alpha-4 gene (COL4A4) was identified in six patients and it co-segregated with the disease in this family. The variant is predicted to be disease-causing and results in collagen IV abnormalities. Our finding broadens mutation spectrum of the COL4A4 gene and extends the phenotypic spectrum of collagen IV nephropathies. Our study suggests that exome sequencing is a cost-effective and efficient approach for identification of disease-causing mutations in phenotypically complex or equivocal disorders. Timely screening for COL4A3/COL4A4 mutations in patients with familial FSGS may help both accurately diagnose and treat these patients., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.

To examine the association between the sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) gene, and Parkinson's disease (PD) in Han Chinese from Central South part of Mainland China, we performed systematic genetic analysis in 502 Chinese Han patients with PD and 637 gender-, age-, and ethnicity-matched normal controls from Central South part of the Mainland China. We identified 11 single nucleotide variants and Leu-Ala (Val) repeat variants in the SMPD1 gene in our large cohort. Two novel missense variants, c.638A > C (p.H213P) and c.1673T > C (p.L558P), and a rare known missense variant, c.1805G > A (p.R602H, rs370129081), were identified in three sporadic PD cases. None of these three variants were observed in controls. Additionally, case-control analysis showed association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with PD (P = 0.015, χ (2) = 8.451). Our data provide supportive evidence that some genetic variants in SMPD1 increase the risk of PD in the Chinese Han population.

Febrile seizures (FS), the most frequent type of seizures in children, occur in neurologically normal infants and children between the ages of 3 months and 5 years with genetic predisposition. The aim of this study was to identify the responsible gene in a four-generation Chinese Han pedigree with autosomal dominant FS. Seven family members (three affected and four unaffected) were enrolled in this study. Exome sequencing was conducted and a duplication mutation c.649dupC (p.R217Pfs*8) in the proline-rich transmembrane protein 2 gene (PRRT2) was identified. The mutation co-segregated with the disorder and was absent in normal controls. To our knowledge, this is the first report of a pedigree with complete penetrance of FS, which is caused by mutation in the PRRT2 gene. FS is a novel phenotype of the c.649dupC (p.R217Pfs*8) mutation. Our discovery broadens the spectrum of genetic causes of FS and the spectrum of phenotypes linked to mutation in the PRRT2 gene.

Parkinson's disease (PD) is the second most common chronic neuronal degeneration disorder with motor and nonmotor clinical features. The rs10788972 variant of the transcription elongation factor A (SII) N-terminal and central domain containing 2 (TCEANC2) gene in the PARK10 region was recently identified to be strongly related to sporadic PD in the American population. To evaluate whether the same variant is associated with sporadic PD in Chinese Han population, we researched 513 sporadic PD patients and 512 normal controls of Chinese Han ethnicity in Mainland China. No significant difference in genotypic and allelic distributions between patients and control groups for either rs10788972 (for genotypic distribution, χ(2) = 0.412, p = 0.814, and for allelic distribution, χ(2) = 0.280, p = 0.597) or its neighbor marker rs12046178 (for genotypic distribution, χ(2) = 1.500, p = 0.472, and for allelic distribution, χ(2) = 1.339, p = 0.247) was found. Our data suggest that neither variant is related to sporadic PD in Chinese Han population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder. It is characterized by selective loss of dopamine-producing neurons and aggregation of alpha-synuclein (SNCA) in neurons of particular brain regions. At least 20 loci and 15 disease-causing genes have been identified. Rare missense or multiplication mutations in the SNCA gene have been reported to be involved in some familial and sporadic cases of PD. More recently, two novel pathogenic missense mutations (p.H50Q and p.G51D) were identified in the SNCA gene. To evaluate whether mutation(s) in the coding region of SNCA gene is related to PD in Chinese population, we investigated the SNCA gene in 502 PD patients of Chinese Han ethnicity from Mainland China. No pathogenic mutation was identified in the coding region of the gene. A known G to A transition (c.306 + 66G>A, rs10005233) in the intron 4, which does not potentially change splicing, was identified. Our data indicate that mutations in the coding region of the SNCA gene are not likely to be a common cause of PD in Chinese population.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized clinically by bradykinesia, resting tremor, rigidity and postural instability. Mutations in the ATPase 13A2 gene were found to be the causes for the Kufor-Rakeb syndrome, a rare form of recessively inherited atypical juvenile parkinsonism. The ATPase Na(+)/K(+) transporting beta 4 polypeptide gene (ATP1B4) is located within a 19-centimorgen region of the PARK12 near the marker DXS1001 and it encodes a protein named βm, a member of P-type ATPases β-subunit family. To determine whether mutations in the ATP1B4 gene are associated with PD, we screened the coding region of this gene in 100 Chinese Han patients with PD. A known single nucleotide variant rs2072452 (c.143T > C), predicted to lead to amino acid substitution (p.Val48Ala), was identified. Extended analysis of 202 patients with PD and 400 gender, age, and ethnicity matched healthy controls showed no significant differences between patients and control subjects for genotypic and allelic distributions (P = 0.638 for genotypic distribution; P = 0.685 for allelic distribution in females and P = 0.303 for allelic distribution in males), suggesting the variant in the coding region of the ATP1B4 gene may play little or no role in the development of PD in Chinese Han population.

Alport syndrome (AS) is a monogenic disease of the basement membrane (BM), resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3), the collagen type IV alpha-4 gene (COL4A4), and the collagen type IV alpha-5 gene (COL4A5), which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36) in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy) were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD). Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

Background and Purpose: Exome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family. Because of the clinical overlap between ET and Parkinson's disease (PD), the role of FUS in an independent cohort of PD patients from China mainland was evaluated., Methods: The entire coding region of FUS in 508 Chinese Han patients with PD and the identified variants in 633 normal controls were evaluated. A variant was further screened in an additional 382 controls for the frequency in our population., Results: A novel variant c.696C > T (p.Y232Y) in 2 sporadic patients with PD and six variants (c.52C > A, p.P18T; c.52C > T, p.P18S; c.147C > A, p.G49G; c.291C > T, p.Y97Y; c.684C > T, p.G228G; c.1176G > A, p.M392I) without significant difference in genotypic and allelic distributions in our PD cohort were identified., Conclusion: The FUS gene is not a genetic risk factor for PD in the population of Chinese Han ethnicity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The F-box only protein 48 gene (FBXO48) is located in 2p13.3, the disease gene locus of Parkinson disease type 3 (PARK3), and it is one of the paralogs of the F-box only protein 7 gene (FBXO7), which is a causative gene of the Parkinson disease type 15 (PARK15; also known as Parkinsonian-pyramidal disease, PPD). To determine whether genetic mutation in the coding region of the FBXO48 gene plays a role in the etiology of PD, we screened DNA samples from 350 Chinese Han patients with PD. No mutation in the coding region of the FBXO48 gene was identified in our PD cohort, suggesting that mutations in the coding region of the FBXO48 gene play little or no role in the development of PD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Tourette syndrome/chronic tic phenotype (TS-CTD) is a neurological disorder manifested particularly by motor and vocal tics and associated with a variety of behavioral abnormalities. Recently, the mitochondrial ribosomal protein L3 gene (MRPL3) S75N, the DnaJ (Hsp40) homolog subfamily C member 13 gene (DNAJC13) A2057S, the orofacial cleft 1 candidate 1 gene (OFCC1) R129G and c.-5A>G variants are reported to be associated with Tourette syndrome/chronic tic phenotype (TS-CTD) in patients of European ancestry. To evaluate whether these variants are associated with TS-CTD in Chinese Han patients, we screened 132 Chinese Han patients from Mainland China. None of the 132 samples from patients with TS-CTD showed the MRPL3 S75N, DNAJC13 A2057S, OFCC1 R129G and c.-5A>G variants, and these variants probably are a rare cause of TS-CTD in a Chinese Han ethnic group. Genetic heterogeneity of TS should be considered and tests designed to detect these variants in Chinese Han ethnic group probably will not have a diagnostic utility in clinical practice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Tourette Syndrome (TS) is a complex neuropsychiatric disorder characterized by vocal and motor tics. While environmental causes have been proposed to play a role, genetic factors are believed to be the main determinants of the disorder and its clinical manifestations. Recently, a heterozygous W317X mutation in the histidine decarboxylase gene (HDC) was reported to be responsible for TS in a two-generation pedigree. To investigate whether the HDC gene play a role in TS in Chinese Han population, we performed genetic analysis of the coding region of the HDC gene in 100 Chinese Han patients with TS. Three variants were found including a C > T transition (IVS1 + 52C > T), a novel C > A transition (c.426C > A) in exon 4, and a novel G > A transition (c.1743G > A) in exon 12, both predicted with no amino acid change. Extended analysis was conducted in a total of 120 TS patients and 240 sex, age, and ethnicity matched healthy controls. No significant differences in genotypic and allele distribution between patients and controls for these three variants (P = 0.274, P = 1.000 and P = 0.632 for genotypic distribution, respectively; P = 0.143, P = 1.000 and P = 0.582 for allele distribution, respectively) were observed, suggesting variants in the HDC gene may play little or no role in TS susceptibility in Chinese Han population., (Copyright © 2011 Wiley Periodicals, Inc.)

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ²)=6.446, p=0.040 for genotypic distribution; χ²=5.762, p=0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Essential tremor (ET) has been hypothesized to be a risk factor for the development of Parkinson disease (PD). Recently, rs9652490 variant in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was found to be associated with ET susceptibility. To evaluate whether the same variant is associated also with PD susceptibility, we investigated the association between the LINGO1 rs9652490 variant and PD phenotype in Caucasian and Chinese PD subjects. We found no significant differences in genotypic and allele distribution between patients and control subjects (χ(2)=1.931, p=0.381 for genotypic distribution; χ(2)=0.001, p=0.973 for allele distribution), suggesting this variant is not associated with PD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)