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result(s) for
"Consanguinity."
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Consanguinity in context
\"An essential guide to this major contemporary issue, Consanguinity in Context is a uniquely comprehensive account of intra-familial marriage. Detailed information on past and present religious, social, and legal practices and prohibitions is presented as a backdrop to the preferences and beliefs of the 1100+ million people in consanguineous unions. Chapters on population genetics, and the role of consanguinity in reproductive behaviour and genetic variation, set the scene for critical analyses of the influence of consanguinity in the early years of life. The discussion on consanguinity and disorders of adulthood is the first review of its kind and is particularly relevant given the ageing of the global population. Incest is treated as a separate issue, with historical and present-day examples examined. The final three chapters deal in detail with practical issues, including genetic testing, education and counselling, national and international legislation and imperatives, and the future of consanguineous marriage worldwide\"-- Provided by publisher.
Book
Runs of homozygosity: windows into population history and trait architecture
Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.
Journal Article
Prevalence and factors contributing to consanguineous marriages in Morocco/Pr valence des mariages consanguins et facteurs contribuants au Maroc
M thodes : La pr sente tude analytique transversale a permis de recueillir des donn es sur le mariage consanguin aupr s de 453 femmes marocaines mari es g es de 18 ans ou plus, au moyen d'un questionnaire structur administr par un enqu teur, et d'analyser ces donn es l'aide du logiciel SPSS version 26. [phrase omitted]
Journal Article
Negotiating risk
Drawing on fieldwork with British Pakistani clients of a UK genetics service, this book explores the personal and social implications of a ‘genetic diagnosis’. Through case material and comparative discussion, the book identifies practical ethical dilemmas raised by new genetic knowledge and shows how, while being shaped by culture, these issues also cross-cut differences of culture, religion and ethnicity. The book also demonstrates how identifying a population-level elevated ‘risk’ of genetic disorders in an ethnic minority population can reinforce existing social divisions and cultural stereotypes. The book addresses questions about the relationship between genetic risk and clinical practice that will be relevant to health workers and policy makers.
eBook
Whole-Transcriptome Analysis by RNA Sequencing for Genetic Diagnosis of Mendelian Skin Disorders in the Context of Consanguinity
Abstract
Background
Among the approximately 8000 Mendelian disorders, >1000 have cutaneous manifestations. In many of these conditions, the underlying mutated genes have been identified by DNA-based techniques which, however, can overlook certain types of mutations, such as exonic-synonymous and deep-intronic sequence variants. Whole-transcriptome sequencing by RNA sequencing (RNA-seq) can identify such mutations and provide information about their consequences.
Methods
We analyzed the whole transcriptome of 40 families with different types of Mendelian skin disorders with extensive genetic heterogeneity. The RNA-seq data were examined for variant detection and prioritization, pathogenicity confirmation, RNA expression profiling, and genome-wide homozygosity mapping in the case of consanguineous families. Among the families examined, RNA-seq was able to provide information complementary to DNA-based analyses for exonic and intronic sequence variants with aberrant splicing. In addition, we tested the possibility of using RNA-seq as the first-tier strategy for unbiased genome-wide mutation screening without information from DNA analysis.
Results
We found pathogenic mutations in 35 families (88%) with RNA-seq in combination with other next-generation sequencing methods, and we successfully prioritized variants and found the culprit genes. In addition, as a novel concept, we propose a pipeline that increases the yield of variant calling from RNA-seq by concurrent use of genome and transcriptome references in parallel.
Conclusions
Our results suggest that “clinical RNA-seq” could serve as a primary approach for mutation detection in inherited diseases, particularly in consanguineous families, provided that tissues and cells expressing the relevant genes are available for analysis.
Journal Article
ZFYVE19 gene mutation: A novel variant of progressive familial intrahepatic cholestasis
A recent nonsyndromic phenotype, newly linked to mutations in the ZFYVE19 gene, is characterized by the appearance of cholestasis accompanied by an increase in serum gamma‐glutamyltranspeptidase (GGT) from infancy or early childhood. Affected individuals generally present with hepatosplenomegaly and may develop portal hypertension. The disease is thought to be the result of cholangiocyte‐specific ciliary dysfunction, indicating a ciliopathy that appears to be limited to the liver. Here, we describe the case of an infant born to first‐degree consanguineous parents, in whom neonatal cholestasis accompanied by elevated GGT led to the discovery of a ZFYVE19 deficiency. The diagnosis was established following an in‐depth analysis of the complete exome sequencing.
Journal Article
Consanguinity and adverse fetal outcomes- a population-based cohort study from a multiethnic population in the Middle East
Background
Consanguinity occurs widely in the Middle East and is associated with reproductive loss, congenital malformations, metabolic disorders, and autosomal recessive disorders. Qatar has a high consanguinity rate; however, large-scale population-based studies evaluating perinatal outcomes are lacking.
Methods
A retrospective cohort study of pregnancies ≥ 20 weeks of gestational age in Qatar from a maternity registry was conducted. Women were divided into consanguineous unions (CU) and non-consanguineous unions (NCU) based on their relationship with their spouses. The CUs were further divided into first-degree and second-degree. The outcomes included congenital anomalies, chromosomal anomalies, preterm births, stillbirths, neonatal deaths and small for gestational age (SGA).
Results
The rate of consanguinity among the women in the cohort was 30.8% (46.4% among Qatari women), with higher rates of first-degree (74%). Younger maternal age, obesity, higher parity and lower maternal education were factors associated with CUs. The incidences of anomalies, stillbirth and neonatal deaths in CUs were 21, 4.3 and 2.4 per 1000 births, respectively. After adjusting for confounders, CUs had higher odds of major congenital anomalies (aOR = 1.37;
p
= 0.049), stillbirth (aOR = 3.10,
p
= 0.007) and neonatal deaths (aOR = 3.15,
p
= 0.042) in non-anomalous babies, the difference being larger in non-Qatari women. Cardiovascular anomalies were most common, higher in first-degree CU, with nervous system anomalies higher in expatriates.
Conclusions
This study concludes that consanguinity is associated with an array of major risks, including congenital anomalies, stillbirths, and neonatal deaths, even in morphologically normal babies. The results are intended to raise awareness about the consequences of CUs in the country, in order to improve the genetic constitution and long-term health of future generations.
Journal Article
Health and population effects of rare gene knockouts in adult humans with related parents
Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.
Journal Article
Network of large pedigrees reveals social practices of Avar communities
From
ad
567–568, at the onset of the Avar period, populations from the Eurasian Steppe settled in the Carpathian Basin for approximately 250 years
1
. Extensive sampling for archaeogenomics (424 individuals) and isotopes, combined with archaeological, anthropological and historical contextualization of four Avar-period cemeteries, allowed for a detailed description of the genomic structure of these communities and their kinship and social practices. We present a set of large pedigrees, reconstructed using ancient DNA, spanning nine generations and comprising around 300 individuals. We uncover a strict patrilineal kinship system, in which patrilocality and female exogamy were the norm and multiple reproductive partnering and levirate unions were common. The absence of consanguinity indicates that this society maintained a detailed memory of ancestry over generations. These kinship practices correspond with previous evidence from historical sources and anthropological research on Eurasian Steppe societies
2
. Network analyses of identity-by-descent DNA connections suggest that social cohesion between communities was maintained via female exogamy. Finally, despite the absence of major ancestry shifts, the level of resolution of our analyses allowed us to detect genetic discontinuity caused by the replacement of a community at one of the sites. This was paralleled with changes in the archaeological record and was probably a result of local political realignment.
Analysis of ancient DNA from 424 individuals in the Avar period, from the sixth to the ninth century AD, reveals population movement from the steppe and the prolonged existence of a steppe nomadic descent system centred around patrilineality and female exogamy in central Europe.
Journal Article
The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes
In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving
ITPR1
,
VAMP1
,
MCTP2
, and
TBP
). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (
ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1,
and
WHSC1
) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (
AKAP6
in intellectual disability and
UBR4
in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations.
Journal Article