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.

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

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.

Genome-wide linkage screen of a consanguineous multiple sclerosis kinship

2003 ◽  
Vol 9 (2) ◽  
pp. 128-134 ◽  
Author(s):  
H Modin ◽  
T Masterman ◽  
T Thorlacius ◽  
M Stefánsson ◽  
A Jónasdóttir ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Linkage Analysis ◽  
Autosomal Recessive ◽  
Index Case ◽  
A Priori ◽  
Family Members ◽  
Chromosome 9 ◽  
Genome Wide ◽  
Healthy Siblings ◽  
Affected Subject

Multiple sclerosis (MS), like A lzheimer’s disease (A D) and Parkinson’s disease (PD), is a common neurological disorder thought to be caused by the interaction of several genes with unknown environmental factors. In both A D and PD the identification of disease forms inherited in a classic Mendelian fashion has helped investigators elucidate pathogenetic mechanisms. In this study a whole-genome screen, with an average of 608 successful genotypes per person, was performed on nine members of a consanguineous family: the index case, three of her siblings and her daughter, all of whom have been diagnosed with definite MS; as well as the parents of the index case (first cousins), one of her five healthy siblings and her husband (who is also her first cousin). Nonparametric linkage analysis was performed on genotyping data. Based on the presence of consanguinity, the a priori hypothesis was that the disease is transmitted in an autosomal recessive fashion in the pedigree. Linkage analysis revealed a suggestive logarithm of odds (LO D) score of 2.29 on the long arm of chromosome 9. Four of five affected family members were identically homozygous for a haplotype under this peak, spanning approximately 43 cM, while the fifth affected subject and all unaffected family members were hetero zygous for the haplotype.

scholarly journals The PR Interval is a Heritable Quantitative Trait with Evidence for Linkage to Chromosome 4 in a Genome-Wide Scan: the Framingham Heart Study

Circulation ◽  
2001 ◽  
Vol 103 (suppl_1) ◽  
pp. 1354-1354
Author(s):  
Christopher J. O’Donnell ◽  
Emelia J. Benjamin ◽  
Diane Corey ◽  
Christopher Newton-Cheh ◽  
Daniel Levy ◽  
...  
Keyword(s):  
General Population ◽  
Framingham Heart Study ◽  
Heart Block ◽  
Chromosome 4 ◽  
Interval Prolongation ◽  
Lod Score ◽  
Genome Wide ◽  
Heart Study ◽  
Pr Interval ◽  
Genome Wide Scan

P19 Introduction: Delayed atrioventricular conduction on the electrocardiogram (ECG), manifested by PR interval prolongation, can progress to heart block. Both heart-rate slowing drugs and environmental factors may lead to PR interval prolongation; however, the heritability of the PR interval has not been studied in the general population and genetic variants in the regulation of PR duration have not been characterized. Methods: We examined the heritability of the PR interval and we tested for evidence of linkage of the PR interval to chromosomal regions in a large population-based cohort. 12-lead ECGs were obtained routinely in adult Framingham Heart Study participants as part of the clinic examination. The PR interval was measured using digital calipers. We conducted a 10 cM genome wide scan in 328 extended families (1688 genotyped subjects, 2257 phenotyped subjects, 2028 phenotyped sibling pairs). Variance component methods were used to estimate heritability and to perform linkage analysis. Results: The PR interval (adjusted for age and RR-interval) was heritable [h 2 0.32 (95% confidence interval 0.26-0.37)]. The highest multipoint LOD score for the adjusted PR interval was found on chromosome 4 (LOD score was 2.16 at 123 cM). The next highest LOD score was 1.88 (chromosome 17 at 59 cM). Conclusion: These results suggest there are influential genetic regions contributing to variability in PR interval in the general population. Defining genetic determinants of PR duration may provide insights into the pathophysiology of heart block and may help identify persons with a high susceptibility to drug-induced heart block.

scholarly journals Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation

Genomics ◽  
2008 ◽  
Vol 92 (5) ◽  
pp. 273-278 ◽  
Author(s):  
Lynn Petukhova ◽  
Edilson C. Sousa ◽  
Amalia Martinez-Mir ◽  
Anna Vitebsky ◽  
Lina G. dos Santos ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Autosomal Recessive ◽  
Genome Wide

Quantitative trait loci for human muscle strength: linkage analysis of myostatin pathway genes

2005 ◽  
Vol 22 (3) ◽  
pp. 390-397 ◽  
Author(s):  
W. Huygens ◽  
M. A. I. Thomis ◽  
M. W. Peeters ◽  
J. Aerssens ◽  
R. Vlietinck ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Linkage Analysis ◽  
Quantitative Trait ◽  
Single Point ◽  
Linkage Study ◽  
Human Muscle ◽  
Lod Score ◽  
Strong Inhibitor ◽  
Myostatin Gene ◽  
Multipoint Linkage

This study reports the results of a multipoint linkage study that aims to unravel the genetic basis of muscle strength and muscle mass in humans. Myostatin ( GDF8) is known to be a strong inhibitor of muscle growth in animals. However, studies examining human myostatin polymorphisms are rare and are limited to the GDF8 gene itself. Here, the contribution to isometric and concentric knee strength of nine key proteins involved in the myostatin pathway is studied in a nonparametric multipoint linkage analysis by means of a variance components and regression method. A sample of 367 healthy young male siblings was phenotyped on an isokinetic dynamometer and genotyped for markers of the myostatin pathway genes. Three of the loci were found significantly linked with a quantitative trait locus (QTL) for knee muscle strength. First, D13S1303 showed replication of an explorative single-point linkage study with a maximum LOD score of 2.7 ( P = 0.0002). Second, maximum LOD scores of 3.4 ( P = 0.00004) and 3.3 ( P = 0.00005) were observed for markers D12S1042 and D12S85, respectively, at 12q12–14. Finally, marker D12S78 showed an LOD score of 2.7 at 12q22–23. We conclude that several genes involved in the myostatin pathway, but not the myostatin gene itself, are important QTLs for human muscle strength. An additional set of valuable candidate genes that were not part of the myostatin pathway was found in the chromosome 12 and 13 genomic regions.

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.

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.

scholarly journals First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Dominika Oziębło ◽  
Anna Sarosiak ◽  
Marcin L. Leja ◽  
Birgit S. Budde ◽  
Grażyna Tacikowska ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Linkage Analysis ◽  
Segregation Analysis ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
German Family ◽  
Clinical Exome Sequencing ◽  
Genome Wide ◽  
Syndromic Hearing Loss ◽  
Family Segregation

Abstract Background Biallelic PTPRQ pathogenic variants have been previously reported as causative for autosomal recessive non-syndromic hearing loss. In 2018 the first heterozygous PTPRQ variant has been implicated in the development of autosomal dominant non-syndromic hearing loss (ADNSHL) in a German family. The study presented the only, so far known, PTPRQ pathogenic variant (c.6881G>A) in ADNSHL. It is located in the last PTPRQ coding exon and introduces a premature stop codon (p.Trp2294*). Methods A five-generation Polish family with ADNSHL was recruited for the study (n = 14). Thorough audiological, neurotological and imaging studies were carried out to precisely define the phenotype. Genomic DNA was isolated from peripheral blood samples or buccal swabs of available family members. Clinical exome sequencing was conducted for the proband. Family segregation analysis of the identified variants was performed using Sanger sequencing. Single nucleotide polymorphism array on DNA samples from the Polish and the original German family was used for genome-wide linkage analysis. Results Combining clinical exome sequencing and family segregation analysis, we have identified the same (NM_001145026.2:c.6881G>A, NP_001138498.1:p.Trp2294*) PTPRQ alteration in the Polish ADNSHL family. Using genome-wide linkage analysis, we found that the studied family and the original German family derive from a common ancestor. Deep phenotyping of the affected individuals showed that in contrast to the recessive form, the PTPRQ-related ADNSHL is not associated with vestibular dysfunction. In both families ADNSHL was progressive, affected mainly high frequencies and had a variable age of onset. Conclusion Our data provide the first confirmation of PTPRQ involvement in ADNSHL. The finding strongly reinforces the inclusion of PTPRQ to the small set of genes leading to both autosomal recessive and dominant hearing loss.

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