Consanguinity and intellectual and developmental disabilities

Author: A. Bittles
Submitted: Friday 6th of July 2012 10:17:31 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: qc2, qc3


Studies into the influence of consanguinity on intellectual performance have produced quite varied results. In a small-scale USA study no significant effect was observed with respect to mean IQ but there was a significantly higher standard deviation in the IQ scores of first cousin progeny, which ranged from 57 to 154. Subsequent much larger studies into the possible effects of consanguinity on intellectual achievement in Hiroshima and Nagasaki, Japan, which incorporated control for differential socioeconomic status, indicated a decline in the performance of first cousin progeny of 0.20-0.68% in neuromuscular tests by comparison with non-consanguineous children. In terms of school performance the first cousin progeny were 0.09-0.13% less successful than their non-consanguineous counterparts, while WISC psychometric tests indicated a non-significant mean reduction in verbal scores of 2.8% and in performance scores of 2.1%. Comparable results were obtained on the Japanese island of Hirado, Japan but in Shizuoka, Japan there was a negative association between increasing levels of consanguinity and both school performance and IQ, although the results only attained statistical significance for boys. A number of studies in North India reported lower mean IQ scores in first cousin offspring, but in most cases the attempts to ensure socioeconomic comparability of the consanguineous and non-consanguineous subjects were rudimentary. The most convincing demonstration of an adverse effect of consanguinity on cognitive performance was in the Israeli Arab community, with the highest mean performance scores attained by the children of non-consanguineous parents and the lowest by double first cousin progeny (F = 0.125). The findings were consistent with the homozygous expression of specific recessive alleles causing mild to moderate intellectual disability in a minority of consanguineous children. But given the strong negative correlation between consanguinity and socioeconomic status in many societies the poorer performance by the children of consanguineous parents in IQ tests may at least partially be due to non-genetic causes. Intellectual and developmental disability (IDD) is usually subdivided into three sub-categories, i.e. people with a mild level of intellectual disability and IQ scores ranging from 55 to 69 who represent some 85% of the overall IDD population, 10% of cases with moderate disability (IQ score 40-54), and 5% of individuals with severe disability (IQ score <40 points). Globally 0.2% to 4.0% of individuals have mild IDD, with 0.3% to 0.5% of children diagnosed with severe IDD. In both low and high income countries elevated levels of global developmental delay, and mild and severe intellectual and developmental disability, have been consistently associated with parental consanguinity. Autosomal recessive forms of intellectual and developmental disability (ARNSID) account for almost 25% of all non-syndromic cases of IDD, but the extreme heterogeneity of the disorder has greatly hampered the 16 identification of specific mutations. Thirteen genomic regions, MRT (mental retardation) 1-13, have been positively implicated in ARNSID, with the reports mainly originating from consanguineous kindreds that also are members of highly endogamous communities in which founder effects would predictably be observed, e.g. Israeli Arabs, Iranian, Tunisian and Pakistani families, and in a US religious isolate. A further three loci MRT14-16 have been putatively identified in highly endogamous and/or consanguineous Pakistani families and homozygosity mapping has additionally indicated ARNSID loci on chromosomes 9q34, 11p11-q13 and 19q13 in Iran. Severe autosomal dominant forms of intellectual disability usually manifest as sporadic cases since affected individuals rarely reproduce. As half of the estimated 25,000 human genes are believed to be expressed in the brain, the total number of genes associated with ARNSID could potentially run into the thousands. A disease gene for ARNSID identified in an isolated community will often have arisen as a founder mutation, so there is a high likelihood that many causative genes for ARNSID will prove to be restricted in their distribution and expression. However, in Iran some ARNSID mutations may account for several percent of the patients diagnosed, and homozygosity mapping in consanguineous families has identified additional mutations in 23 genes already implicated in IDD or related neurological disorders, with probable IDD-causing gene variants in a further 50 novel candidate genes. Paediatric neurological disorders, including neurometabolic degenerative disorders, have been reported to be elevated in consanguineous progeny. The association with consanguinity is predictable since many cases of progressive encephalopathy, both due to individually rare metabolic diseases and neurodegenerative disorders, have an autosomal recessive mode of inheritance. To date seven genetic loci (MCPH1-7) have been identified in primary microcephaly, with a reduction in the brain sizes of affected individuals to approximately one-third of the expected volume resulting in variable levels of intellectual disability. An initial report suggesting an association between consanguinity and Down syndrome implicated the action of one or more recessive genes involved in the control of mitotic nondisjunction in the homozygous fertilized ovum, or the action of an autosomal recessive gene in homozygous parents that resulted in meiotic nondisjunction. Only five of the subsequent 12 studies conducted in 11 other countries confirmed a positive association between parental consanguinity and Down syndrome. In general, studies which were unable to identify a link between consanguinity and Down syndrome were based on larger sample sizes and had incorporated better control for maternal age. However, as demonstrated in a recent study of a highly endogamous and consanguineous Arab community in Israel, some lingering doubt remains as to whether an as-yet unidentified causative role may exist for consanguinity in the aetiology of Down syndrome in certain populations. References: Alfi OS, Ghang R, Azen SP. (1980). Evidence for genetic control of non-disjunction in man. American Journal of Human Genetics, 32, 477-483. Bashi J. (1977).. Effects of inbreeding on cognitive performance. Nature, 266, 440-442. Bittles AH. (2012). Consanguinity in Context. Cambridge University Press. Bittles AH, Bower C, Hussain R, Glasson EJ. (2007). The four ages of Down syndrome. European Journal of Public Health, 17, 221-225. Eppig C, Fincher CL, Thornhill R. (2010). Parasite prevalence and the worldwide distribution of cognitive ability. Proceedings of the Royal Society Series B, 277, 3801-3808. Mahmood S, Ahmad W, Hassan MJ. (2011). Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. Orphanet Journal of Rare Diseases, 6, 39. Najmabadi H, Hu H, Garshabi M. et al. (2011). Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature, 478, 57-63. Slatis HM, Hoene RE. (1961). The effect of consanguinity on the variation of continuously variable characteristics. American Journal of Human Genetics, 13, 28-31. Schull WJ, Neel JV. (1965). The Effects of Inbreeding on Japanese Children. New York: Harper and Row. Zlotogora J, Shalev SA. (2010). The consequences of consanguinity on the rates of malformations and major medical conditions at birth and in early childhood in inbred populations. American Journal of Medical Genetics, 152A, 2023-8.


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abstract 12Bologna_Bittles_Intellectual_disabillity_5224.pdf

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A. Bittles. Consanguinity and intellectual and developmental disabilities. EUROGENE portal. July 2012. online:



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