An Approach to Inherited Pulmonary Disease
Stephen D. Litwin in Genetic Determinants of Pulmonary Disease, 2020
A high degree of consanguinity in the parents of individuals manifesting a rare phenotype can be an indication of autosomal recessive inheritance. Consanguinity is an estimate of the fraction of the genome in two mates that is identical because they have inherited it from the ancestors they have in common. For example, in a brother and sister about one-half of the autosomal genes are identical by descent, and in first cousins about one-eighth of the autosomal genes are identical. The offspring of such matings would be homozygous at a correspondingly large number of loci; copies of genes that are identical by descent would be "meeting" each other in these offspring. If one of the ancestors that the mates have in common was heterozygous for a gene for a rare recessive phenotype the probability of homozygosity for that gene in the children of a consanguineous mating is greatly increased, just as the probability for homozygosity for any gene present in the common ancestors is increased in those children. When the frequency of heterozygous carriers of the gene for a phenotype is low in the population a high proportion of individuals affected with the phenotype are the products of consanguineous matings. In the latter case consanguinity becomes more probable than random chance as a mechanism for copies of a rare gene to "meet" each other forming a homozygote.
Adenylosuccinate lyase deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The disorder is inherited as an autosomal recessive trait. Consanguinity has been described [1]. The enzyme has been generally assayed by following the conversion of adenylosuccinate to AMP spectrophotometrically [25]. Liver, fibroblasts, and lymphocytes have been used to document the deficiency of enzyme activity in individuals with ASL deficiency [4, 10, 26]. The very different metabolite ratio in the type II patient suggested that the enzyme be assayed with both substrates. It was found that in classic type I ASL deficiency, the activities of the enzyme toward the two substrates are decreased in parallel to about 30 percent of control [9]. In general, the activity of mutant enzymes against both substrates are proportionately decreased, regardless of clinical phenotype [27]. In one study of fibroblasts derived from a patient with a type II genotype, activity against succinylAICAR was about 30 percent of control, but when adenylosuccinate was the substrate, the activity was only 3 percent of control [10], data consistent with the higher concentration of adenylosuccinate in the type II patient.
Future generations
Jessica Mozersky in Risky Genes, 2012
Another reproductive pattern that can lead to an increased incidence of disease among populations is consanguinity (Bittles 2005). Genetically, consanguinity is defined as marriage between people who are second cousins or closer (Modell and Darr 2002). Endogamy and consanguinity are not the same thing, but endogamous populations may also have a history of consanguinity. Consanguineous marriages did play a significant role in the history and development of the Jewish population, and many early biblical marriages were consanguineous for a number of historical reasons (Goodman 1979). First, Jewish communities were often small and isolated from one another. which restricted the choice of marriage partners. Second, government and religious laws prohibited Jews from marrying non-Jews. Third, Jews often chose to marry within families because of socio-economic or religious ties and prearrange these marriages from a young age. Consanguineous marriages can strengthen family ties, allow men and women to find partners with relative ease, protect the woman's status and lead to better and more stable relationships between in-laws (Modell and Darr 2002). Finally, some forms of marriage between family members are sanctioned by Jewish law, known as Halacha (Goodman 1979).
The changing pattern and determinants of declining consanguinity in Jordan during 1990–2012
Published in Annals of Human Biology, 2018
M. Mazharul Islam
The dependent variable of this study is consanguinity, which was derived from the individual questionnaire that asks the ever-married women if they have a blood relation to their husband. The response categories to this question were: (1) First cousin: father’s side, (2) First cousin: mother’s side, (3) First cousin on both father and mother’s side, (4) First cousin on both mother and father’s side, (5) Second cousin: father’s side, (6) Second cousin: mother’s side, (7) Other relation and (8) No relation. Clearly, the first four categories of responses comprised ‘first cousin marriages’. The fifth and sixth categories included second cousins and the seventh category included beyond second cousins (i.e. distant relation). By definition, beyond second cousin marriages or distant relations are also consanguineous, but with a degree of relatedness less than that of second cousin. In this study, consanguineous marriages were defined by combining the first six categories and the seventh category was defined as non-consanguineous marriage.
Applying whole exome sequencing in a consanguineous population with autism spectrum disorder
Published in International Journal of Developmental Disabilities, 2023
Watfa Al-Mamari, Ahmed B. Idris, Khalid Al-Thihli, Reem Abdulrahim, Saquib Jalees, Muna Al-Jabri, Ahlam Gabr, Fathiya Al Murshedi, Adila Al Kindy, Intisar Al-Hadabi, Zandrè Bruwer, M. Mazharul Islam, Abeer Alsayegh
The clinic receives referrals from all over the country and accepts children less than 14 years of age. Patients evaluated through the clinic generally follow the diagnostic flowchart depicted in Figure 1. ASD cases were diagnosed based on the Diagnostic Statistical Manual, Fifth Edition (DSM-5) criteria (American Psychiatric Association 2013). A multidisciplinary team, headed by a senior developmental paediatrician, utilized Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule to confirm the diagnosis of ASD. Patients were further clinically characterized by the contribution of a medical geneticist. Clinical and demographic variables were evaluated for their impact on the diagnostic yield. In our study, multiplex ASD refers to families in which multiple individuals were affected, while simplex ASD refers to families in which only a single individual was affected. Syndromic ASD was assigned to patients with a clinically defined pattern of systemic abnormalities and a neurobehavioral phenotype that could include ASD (Fernandez and Scherer 2017). Consanguinity was defined as the parents of the proband being related as second cousins or closer (Bittles 2001).
The utility of whole exome sequencing in diagnosing neurological disorders in adults from a highly consanguineous population
Published in Journal of Neurogenetics, 2019
Weiyi Mu, Nicoline Schiess, Jennifer L. Orthmann-Murphy, Ayman W. El-Hattab
Retrospective chart review was performed on 24 adults with undiagnosed neurologic disorders who were evaluated at genetics and neurology clinics at Tawam Hospital in Al Ain, United Arab Emirates between 2014 and 2016 and had WES testing. Data regarding clinical symptoms, neuroimaging results, family history, and genetic testing results were collected. Consanguinity was noted if the individual’s parents were second cousins or closer in relation. All patients underwent trio WES if parents were available, and proband-only WES if parents were unavailable, by accredited commercial laboratories in Europe or the United States, namely Baylor Genetics Laboratories in Houston, TX; Prevention Genetics in Marshfield, WI; and Centogene in Rostock, Germany. Potentially causative variants underwent Sanger confirmation, and were classified by the laboratory according to the 2015 American College of Medical Genetics guidelines (Richards et al., 2015). Patients were consented for primary and secondary variants, as recommended by ACMG guidelines (Kalia et al., 2017), identified from WES by the clinical genetics team. If clinically indicated, follow-up familial segregation was performed; this included parental testing to determine if two variants in the same recessive gene were biallelic or confirming segregation of likely pathogenic variants in affected siblings. Each of the WES cases were deemed “positive” if a likely disease-causing variant was identified and “negative” if no causative variants were identified. This study was approved by the Al-Ain Medical District Human Research Ethics Committee.