scholarly journals Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Wang ◽  
Xuejuan Chen ◽  
Tao Jiang ◽  
Yayun Gu ◽  
Xiaohan Zhang ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Childhood Onset ◽  
Lod Score ◽  
Genome Wide ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
The Family ◽  
Log Odds ◽  
Normal Controls ◽  
Linkage Interval

Abstract Background Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS. Methods Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family. Results Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls. Conclusion LRP2 is a novel candidate genetic cause of non-syndromic familial CS.

scholarly journals A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21

2021 ◽  
Vol 46 (2) ◽  
Author(s):  
Claudio Toma ◽  
Alex D. Shaw ◽  
Anna Heath ◽  
Kerrie D. Pierce ◽  
Philip B. Mitchell ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Linkage Analysis ◽  
Rare Variants ◽  
Linkage Signal ◽  
Risk Variants ◽  
Genome Wide ◽  
Whole Exome ◽  
Family Based ◽  
Coding Variants ◽  
Linkage Interval

Background: Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness. Methods: Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a genebased segregation test. Results: We identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014). Limitations: We did not examine non-coding variants, but they may explain the remaining linkage signal. Conclusion: Combining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

scholarly journals Pedigree-Based Gene Mapping Supports Previous Loci and Reveals Novel Suggestive Loci in Specific Language Impairment

2020 ◽  
Vol 63 (12) ◽  
pp. 4046-4061
Author(s):  
Erin M. Andres ◽  
Kathleen Kelsey Earnest ◽  
Shelley D. Smith ◽  
Mabel L. Rice ◽  
Muhammad Hashim Raza
Keyword(s):  
Linkage Analysis ◽  
Language Impairment ◽  
Specific Language Impairment ◽  
Suggestive Linkage ◽  
Lod Score ◽  
Specific Language ◽  
Parametric Linkage Analysis ◽  
Genome Wide ◽  
Age Appropriate ◽  
Language Measure

Purpose Specific language impairment (SLI) is characterized by a delay in language acquisition despite a lack of other developmental delays or hearing loss. Genetics of SLI is poorly understood. The purpose of this study is to identify SLI genetic loci through family-based linkage mapping. Method We performed genome-wide parametric linkage analysis in six families segregating with SLI. An age-appropriate standardized omnibus language measure was used to categorically define the SLI phenotype. Results A suggestive linkage region replicated a previous region of interest with the highest logarithm of odds (LOD) score of 2.40 at 14q11.2-q13.3 in Family 489. A paternal parent-of-origin effect associated with SLI and language phenotypes on a nonsynonymous single nucleotide polymorphism (SNP) in NOP9 (14q12) was reported previously. Linkage analysis identified a new SLI locus at 15q24.3-25.3 with the highest parametric LOD score of 3.06 in Family 315 under a recessive mode of inheritance. Suggestive evidence of linkage was also revealed at 4q31.23-q35.2 in Family 300, with the highest LOD score of 2.41. Genetic linkage was not identified in the other three families included in parametric linkage analysis. Conclusions These results are the first to report genome-wide suggestive linkage with a total language standard score on an age-appropriate omnibus language measure across a wide age range. Our findings confirm previous reports of a language-associated locus on chromosome 14q, report new SLI loci, and validate the pedigree-based parametric linkage analysis approach to mapping genes for SLI. Supplemental Material https://doi.org/10.23641/asha.13203218

High Levels of Protein C Are Determinated by PROCR H3 in a Dutch Family.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2139-2139
Author(s):  
Maria Carolina Pintao ◽  
Sara Roshani ◽  
Marieke C.H. de Visser ◽  
Cris Tieken ◽  
Michael W.T. Tanck ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Candidate Genes ◽  
Protein C ◽  
Transmembrane Domain ◽  
Family Members ◽  
Endothelial Protein C Receptor ◽  
Lod Score ◽  
Chromosome 20 ◽  
The Family ◽  
The Mean

Abstract Abstract 2139 Poster Board II-116 The natural anticoagulant protein C (PC) circulates in blood at a concentration of about 60 nM. Inter-individual variations in the levels of PC are in part genetically determined, but which loci in the genome are involved is only partially known. In a recent study we identified a locus on chromosome 20 which was associated with high PC levels in a large pedigree from the GENES study (LOD score >5 at 55 cMorgan). Candidate genes related to the PC pathway under the LOD-1 region encoded FOXA2 (previously known as HNF3 beta, a nuclear factor regulating protein C gene transcription), thrombomodulin (THBD,which is key to activation of PC), and the endothelial protein C receptor (PROCR). Here we present data that pinpoint a SNP in PROCRas being responsible for the observed segregation of high PC levels. The pedigree has 218 members and was ascertained through a proband with a family history of venous thrombosis (VT). Classical genetic risk factors for thrombosis (i.e. PC-, PS-, antithrombin deficiency, factor V Leiden and prothrombin G20201A) were not present. Complete medical data, plasma measurements and DNA was available for 161 family members. The mean age was 47±15 (range 15-87) years. The mean PC plasma level was 116±25% (range 72-212). Four family members had experienced VT and 2 had had recurrence. These symptomatic members had normal to high PC levels (66, 82, 114 and 178%).Haplotypes (and genotypes) for PROCR were determined in the family members by TaqMan assay using tag SNPs (single nucleotide polymorphisms) and PROCR H3 was associated with the levels of PC in the family. Furthermore, the promoter, exons, and 3`UTR of the 3 candidate genes were sequenced in 13 individuals, 9 with high and 4 with normal plasma PC levels. Critical SNPs that were encountered during sequencing were genotyped in all family members, namely FOXA2 rs1055080 (3`UTR) and rs2277764 (promoter region). As those 2 SNPs were inherited together in the set of 13 patients and also in the LETS (data not shown), our further analysis used only rs1055080. Plasma soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) levels were measured with an ELISA assay. PC and sEPCR and levels were compared between PROCR H3 and FOXA2 rs1055080 carriers and non carriers by Student's t-test. sTM was analyzed by Mann-Whitney test. Association between PC levels and sEPCR/sTM levels were evaluated using linear regression analysis. Afterwards associations were adjusted for the PROCR H3 and FOXA2 rs1055080 SNP separately to detect their possible confounding effect. DNA sequencing only yielded previously reported SNPs in FOXA2, THBD and PROCR. Only the above mentioned SNPs were associated with PC plasma levels. Linkage analysis for PC levels using the original markers (from Marshifield) and adding the new PROCR and FOXA2 SNPs did not change the LOD score. When the analysis was adjusted for the mentioned markers, the LOD score dropped below 2. sEPCR has a bimodal distribution; mean ± SD was 103±27 ng/ml for the first mode and 262±70 ng/ml for the second mode. Median (range) sTM was 1.2 ng/ml (0.1-4). Linkage analysis for sEPCR levels yielded a high LOD score (above 6) that was accentuated to above 8 when PROCR H3 was included as a marker. For sTM, the LOD score was low with every combination of markers. PC, sEPCR and sTM levels were compared between PROCR H3 carriers and non-carriers and both PC levels and sEPCR levels were influenced by this PROCR haplotype, but not sTM. In conclusion, chromosome 20 harbors a locus which influences PC levels and also the levels of sEPCR, but not the levels of sTM. A detailed analysis with SNPs in PROCR, THBD and FOXA2suggests that the so-called PROCR H3 is directly responsible for the increased PC and sEPCR levels in this family. PROCR H3 is known to represent a g.A6936G substitution leading to a p.Ser219Gly replacement in the transmembrane domain of EPCR. The Gly219 isoform is more sensitive to sheddases (such as the ADAM17 metalloprotease) and is associated with generation of truncated mRNA lacking the transmembrane domain. However, the exact mechanism by which EPCR and sEPCR levels influence the level of PC remains to be determined Disclosures: No relevant conflicts of interest to declare.

scholarly journals PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study

2003 ◽  
Vol 88 (5) ◽  
pp. 2274-2280 ◽  
Author(s):  
Hassen Hadj Kacem ◽  
Ahmed Rebai ◽  
Noureddine Kaffel ◽  
Saber Masmoudi ◽  
Mohamed Abid ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Transmembrane Protein ◽  
Susceptibility Gene ◽  
Association Test ◽  
Lod Score ◽  
Autoimmune Thyroid ◽  
The Family ◽  
Family Based ◽  
Idiopathic Myxedema ◽  
Pds Gene

Autoimmune thyroid disease (AITD), including Graves’ disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, is caused by multiple genetic and environmental factors. Genes involved in immune response and/or thyroid physiology appear to influence susceptibility to disease. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goiter), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of PDS gene in the genetic susceptibility of AITD, we examined four microsatellite markers in the gene region. Two hundred thirty-three unrelated patients (GD,141; HT, 54; primary idiopathic myxedema, 38), 15 multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (P = 10−3) and HT (P = 1.07 10−24), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test are in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). Multipoint nonparametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients [Z = 2.12, LOD = 0.81, P = 0.026]. Single-point and multipoint parametric LOD score linkage analysis was also performed. Again, the highest multipoint parametric LOD score was found for marker D7S496 (LOD = 1.23; P = 0.0086) in families segregating for GD under a dominant model. This work suggests that the PDS gene should be considered a new susceptibility gene to AITDs with varying contributions in each pathology.

scholarly journals Genome‐wide linkage analysis and whole‐exome sequencing identifies anITGA2Bmutation in a family with thrombocytopenia

2019 ◽  
Vol 186 (4) ◽  
pp. 574-579
Author(s):  
Rami Khoriaty ◽  
Ayse B. Ozel ◽  
Shweta Ramdas ◽  
Charles Ross ◽  
Karl Desch ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Wide ◽  
Whole Exome

scholarly journals Genetic Analysis of a Large Family with Migraine, Vertigo, and Motion Sickness

2019 ◽  
Vol 46 (5) ◽  
pp. 512-517 ◽  
Author(s):  
Leema Reddy Peddareddygari ◽  
Phillip D. Kramer ◽  
Philip A. Hanna ◽  
Mark A. Levenstien ◽  
Raji P. Grewal
Keyword(s):  
Linkage Analysis ◽  
Motion Sickness ◽  
Autosomal Recessive ◽  
Large Family ◽  
American Family ◽  
Chromosome 4 ◽  
Microsatellite Repeat ◽  
Lod Score ◽  
Genome Wide ◽  
Multipoint Linkage

ABSTRACT:Background: Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility. Methods: Genome-wide linkage analysis performed using 400 microsatellite repeat markers spaced at 10 cM throughout the genome. The members of this family were phenotyped for each condition, migraine, vertigo, and motion sickness and analyzed separately. Statistical analysis was performed using two-point and multipoint linkage analysis employing a number of models including autosomal recessive or dominant patterns of inheritance with high and low genetic penetrance. Results: We identified a novel locus for migraine, 9q13-q22 (maximum two-point logarithm of odds [LOD] score-2.51). In addition, there are suggestive LOD scores that localize to different chromosomes for each phenotype; vertigo (chromosome 18, LOD score of 1.82) and motion sickness (chromosome 4, LOD score of 2.09). Conclusions: Our analysis supports our hypothesis that the migraine-associated vertigo and motion sickness may involve distinct susceptibility genes.

Genome Wide Linkage Analysis Suggests Genetic Heterogeneity in Autosomal Recessive Dyskeratosis Congenita, with One Locus on Chromosome 15.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1054-1054
Author(s):  
Amanda Walne ◽  
Tom Vulliamy ◽  
Anna Marrone ◽  
Inderjeet Dokal
Keyword(s):  
Bone Marrow ◽  
Linkage Analysis ◽  
Genetic Heterogeneity ◽  
Autosomal Recessive ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Chromosome 15 ◽  
Lod Score ◽  
Genome Wide

Abstract Dyskeratosis congenita (DC) is a severe inherited premature aging syndrome characterised by muco-cutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) forms of the disease are recognised. Mutations in DKC1 and TERC have been identified in X-linked recessive and AD-DC, respectively. The products encoded by both of these genes are key components of the telomerase complex, which is responsible for maintaining telomere length after cell division. This has led to the suggestion that DC is primarily a disease of defective telomere maintenance. The international dyskeratosis congenita registry (Hammersmith Hospital, London) has information on 244 families with DC. Of these 30% have mutations in DKC1 and 6% have mutations in TERC. Disease causing mutations in the remaining 64% of patients have yet to be characterised. In an attempt to identify a candidate locus through homozygosity mapping, we performed a genome-wide scan using a maximum of 475 microsatellite markers (LMS-MD 10/5 ABI PRISM) on DNA from 19 affected individuals from 13 families with consanguineous marriage. No single marker was found to be homozygous in all individuals, although not all markers were typed in all individuals. 19% of markers were homozygous in four or more families across the chromosomes, but this dropped to 4% when the number of families that were homozygous was increased to six. Only six markers (1% approx.) were homozygous in seven or more families. This suggests there is considerable genetic heterogeneity amongst the AR-DC subset. To investigate this further we selected one family that showed a recessive pattern of inheritance with samples available from three affected individuals, three unaffected siblings and parents. Affected members in this family had the classical DC features of nail dystrophy, abnormal skin pigmentation, abnormal dentition and severe bone marrow failure in the index case. To try to identify a disease locus in this family, we typed the whole family at the markers where the affected individuals shared common homozygosity and analysed the data using Genehunter, a multi-point linkage analysis program, to obtain a LOD score (log10 of the odd ratio in favour of linkage). The maximum LOD score obtained for this family was 2.7 on chromosome 15, suggesting that a disease-causing locus is at chromosome 15q14. This particular location seems to be unique to this family as there is no overlap in homozygosity with any other family studied. It remains to be established how many loci there are, and whether a single gene causes DC in many of the AR families, or if each gene identified causes the disease in a small subset of families. In conclusion this work highlights the extent of genetic heterogeneity that exists in DC, with AR-DC being a very heterogeneous subtype which may involve several genes, but the locus of one AR-DC gene has been assigned to chromosome 15q14.

Heritability and Whole Genome Linkage of Pulse Pressure in Chinese Twin Pairs

2012 ◽  
Vol 15 (6) ◽  
pp. 759-766 ◽  
Author(s):  
Wengjie Jiang ◽  
Dongfeng Zhang ◽  
Zengchang Pang ◽  
Shuxia Li ◽  
Haiping Duan ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Pulse Pressure ◽  
Chinese Population ◽  
Molecular Genetic ◽  
Snp Array ◽  
Heritability Estimate ◽  
Linkage Study ◽  
Chromosome 11 ◽  
Lod Score ◽  
Genome Wide

Elevated pulse pressure is associated with cardiovascular disorders and mortality in various populations. The genetic influence on pulse pressure has been confirmed by heritability estimates using related individuals. Recently, efforts have been made in mapping genes that are linked to the phenotype. We report results on our heritability and linkage study conducted on the Chinese population in mainland China where cardiovascular and cerebrovascular diseases are becoming the leading cause of death. A total of 630 pairs of middle-aged Chinese twins were collected for heritability analysis, from which 63 dizygotic twin pairs were randomly selected for genome-wide linkage analysis using Affymetrix 6.0 SNP array. Regression analysis reconfirmed the significant effects of age, sex, and BMI on pulse pressure. Comparison of twin models suggested the parsimonious AE model as the best model with a heritability estimate of 0.45. Genome-wide non-parametric linkage analysis identified three significant linkage peaks on chromosome 11 (lod score 4.06 at 30.5 cM), chromosome 12 (lod score 3.97 at 100.7 cM), and chromosome 18 (lod score 4.01 at 70.7 cM) with the last two peaks closely overlapping with linkage peaks reported by two American studies. In addition, multiple regions with suggestive linkage were identified with many of them overlapping with published linkage regions. Our results provide both epidemiological and molecular genetic evidence for the genetic dissection of pulse pressure in the Chinese population, which could help in fine mapping and in characterizing genes that are involved in the regulation of pulse pressure.

Two Candidate Genes for Low Platelet Count Identified by Genome-Wide Linkage Analysis: Glycoprotein IX and Thrombopoietin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2160-2160
Author(s):  
Swee Lay Thein ◽  
Steve Best ◽  
Stephan Menzel ◽  
Helen Rooks ◽  
Tim D. Spector ◽  
...  
Keyword(s):  
Platelet Count ◽  
Linkage Analysis ◽  
Chinese Patient ◽  
Genetic Determinants ◽  
Lod Score ◽  
Normal Range ◽  
Platelet Counts ◽  
Normal Platelet Count ◽  
Normal Platelet ◽  
Genome Wide

Abstract Although the ’normal’ range of platelet count in a healthy person is quite broad (150 to 400 ×109/L), an individual’s platelet count is maintained within a much narrower range, constantly balanced between thrombopoiesis and senescence. Platelet counts within the normal range have been shown to be largely determined by genetic factors with heritability estimates from twin studies ranging from 0.57 to 0.80. A genome-wide linkage analysis was carried out in a large Asian Indian kindred with β thalassemia to search for genes influencing variation in normal platelet count. Significant linkage is shown at two locations on chromosome 3q with age, sex and β thalassemia adjusted platelet counts. Linkage analysis showed one marker (D3S1309) on chromosome 3q with a lod score of 3.26 and another marker (D3S1282) approximately 30 cM centromeric, with a lod score of 2.52. Multipoint linkage analysis across 90 cM of chromosome 3q identified two peaks across the region with maximum multipoint lod scores of 3.52 and 4.11 under markers D3S1309 and D3S1282, respectively. Two strong candidate genes for platelet variation were identified in the linked region; thrombopoietin (THPO) and glycoprotein IX (GPIX). Resequencing of four individuals revealed five single nucleotide polymorphisms (SNPs) in THPO and one mutation in the transmembrane region of GPIX. Analysis of variance showed that the GPIX mutation and one THPO SNP accounted for 6% and 4% of the variation in platelet count in the kindred, respectively. The THPO SNP lies in the 3′ untranslated region (3′ UTR) of the gene and has not been previously reported. Although no function could be attributed to the THPO SNP it could potentially influence post-transcriptional control of gene expression. The G to A transition in nucleotide 653 (Ref seq NM_000174) resulted in an Ala 156 (GCC) to Thr (ACC) replacement in the GPIX protein. The GPIX mutation was recently identified in a Chinese patient with Bernard-Soulier syndrome (BSS), a rare bleeding disorder characterized by severe thrombocytopenia and giant platelets. The Chinese patient was homozygous for the mutation; however, heterozygous relatives did not show the characteristic BSS symptoms, leading the authors to conclude that the mutation acted under a recessive model of inheritance. Transient transfection studies by the same group confirmed that the mutation prevents GP Ib/IX complex insertion in the cytoplasmic membrane of platelets, and suppresses GPIbα and GPIX expression, but does not cause its intracellular degradation. One copy of the GPIX mutation was found in 300 European individuals with platelet counts within the normal clinical range. Conclusion: Although the genetic determinants of many thrombocythemias and congenital thrombocytopenias have been identified, very little is known about the genetic determinants of normal platelet count variation. The results suggest that two QTLs on chromosome 3q influence platelet count variation in the Asian Indian kindred, with the GPIX transmembrane mutation and the 3′ UTR SNP in THPO, being strong candidates.

TSC22D2 identified as a candidate susceptibility gene of multi-cancer pedigree using genome-wide linkage analysis and whole-exome sequencing

2019 ◽  
Vol 40 (7) ◽  
pp. 819-827 ◽  
Author(s):  
Lan Xiao ◽  
Fang Wei ◽  
Fang Liang ◽  
Qiao Li ◽  
Hao Deng ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Transforming Growth Factor ◽  
Susceptibility Gene ◽  
Snp Array ◽  
Multiple Tumor ◽  
Genome Wide ◽  
Whole Exome

AbstractCancer is a complex disease, which may involve multiple tumor susceptibility genes that mediate the occurrence and development of tumor molecular events. This study aimed to identify new genetic loci using genome-wide linkage analysis and whole-exome sequencing in a rare, large multi-cancer pedigree recently found in China. We performed high-throughput single-nucleotide polymorphism (SNP) array and linkage analyses of 24 core members of this pedigree and found that the disease susceptibility locus in the multi-cancer pedigree was mapped to chromosome 3q24-26. We also used microsatellites to further validate the results of the SNP locus linkage analysis. Furthermore, we sequenced the whole exome of three members in this pedigree and identified a novel mutant of transforming growth factor β stimulated clone 22 domain family, member 2 (TSC22D2, c.-91T-C) cosegregated with the cancer phenotype. This change was at a highly conserved position, and the exome results were validated using linkage analysis. Moreover, we found the histone H4 transcription factor (HINFP) binds to the promoter region of TSC22D2 and may regulate its transcription. In conclusion, our findings are of great significance to the early pathogenesis of tumors and contribute to the search for molecular targets for the early prevention and treatment of tumors.

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