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Homozygosity mapping of autosomal recessive intellectual disability loci in 11 consanguineous Pakistani families

  • Iltaf Ahmed (a1) (a2), Muhammad Arshad Rafiq (a1), John B. Vincent (a1) (a3) (a4), Attya Bhatti (a2), Muhammad Ayub (a5) and Peter John (a2)...

Autosomal recessive intellectual disability (ID) is genetically heterogeneous and most of the genes causing it remain undiscovered.


We have ascertained 11 consanguineous families multiplex for IDs in order to identify new loci for autosomal recessive genes for non-syndromic ID, or to aid pinpointing mutations in known causative gene/loci.


Microarray genotyping (Affymatrix 250K) was performed to identify homozygosity-by-descent (HBD) in all affected families.


Analysis of genotypes revealed 45 potential HBD regions across the families, although these may be rationalised down to 39. Two families share an overlapping HBD region on 7q11.21. In one family, X-linkage also looks plausible, and a new ID gene near the centromere may be a likely cause. In one family, no HBD region was found, and thus we exclude autosomal recessive mutation as the likely cause in this family. Copy-number variation (CNV) was also performed and revealed no CNVs, homozygous or heterozygous, segregating with the phenotype.


The homozygous loci identified in this study might harbour candidate genes for ID in these studied families. Therefore, we are proceeding with next-generation sequencing analysis of the families, using whole-exome approaches, and anticipate that this will identify the causative gene/mutation within the identified HBD regions for many of the families studied here.

Corresponding author
Muhammad Ayub, Department of Psychiatry, Division of Developmental Disabilities, Queen’s University, Kingston, Ontario, Canada. E-mail: Tel: +1 613 549 7944; Fax: +1 613 549 7387;
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1.Ropers, HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 2010;11:161187.
2.Rauch, A, Hoyer, J, Guth, Set al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 2006;140:20632074.
3.Ropers, HH, Hamel, BC. X-linked mental retardation. Nat Rev Genet 2005;6:4657.
4.Lubs, HA, Stevenson, RE, Schwartz, CE. Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet 2012;90:579590.
5.Musante, L, Ropers, HH. Genetics of recessive cognitive disorders. Trends Genet 2014;30:3239.
6.Najmabadi, H, Motazacker, MM, Garshasbi, Met al. Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Hum Genet 2007;121:4348.
7.Rafiq, MA, Ansar, M, Marshall, CRet al. Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan. Clini Genet 2010;78:478483.
8.Kuss, AW, Garshasbi, M, Kahrizi, Ket al. Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum Genet 2011;129:141148.
9.Priest, JH, Thuline, HC, Laveck, GD, Jarvis, DB. An approach to genetic factors in mental retardation. Studies of families containing at least two siblings admitted to a state institution for the retarded. Am J Ment Defic 1961;66:4250.
10.Bartley, JA, Hall, BD. Mental retardation and multiple congenital anomalies of unknown etiology: frequency of occurrence in similarly affected sibs of the proband. Birth Defects Orig Artic Ser 1978;14:127137.
11.Hussain, R, Bittles, AH. The prevalence and demographic characteristics of consanguineous marriages in Pakistan. J Biosoc Sci 1998;30:261275.
12.Lahiri, DK, Bye, S, Nurnberger, JI Jr., Hodes, ME, Crisp, M. A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested. J Biochem Biophys Methods 1992;25:193205.
13.Lin, M, Wei, LJ, Sellers, WR, Lieberfarb, M, Wong, WH, Li, C. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 2004;20:12331240.
14.Seelow, D, Schuelke, M, Hildebrandt, F, Nurnberg, P. HomozygosityMapper – an interactive approach to homozygosity mapping. Nucleic Acids Res 2009;37:W593W599.
15.Lionel, AC, Vaags, AK, Sato, Det al. Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum Mol Genet 2013;22:20552066.
16.Najmabadi, H, Hu, H, Garshasbi, Met al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:5763.
17.Rafiq, MA, Kuss, AW, Puettmann, Let al. Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet 2011;89:176182.
18.Hart, CE, Race, V, Achouri, Yet al. Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 2007;80:931937.
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Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
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