GENETICS OF NEURODEVELOPMENTAL DISORDERS
Anthony P Monaco The Wellcome Trust Center
for Human Genetics, Oxford, United Kingdom
ABSTRACT In my laboratory, we have initiated genetic
studies of complex neurodevelopmental disorders of childhood, including autism, specific language
impairment and dyslexia. We have completed a full genome scan for susceptibility genes in autism and
found strong evidence for linkage to chromosomes 2q, 7q and 16p 1,2,3. We have also found linkage to 7q
in a family with an autosomal dominant speech and language disorder, identified the causative gene
FOXP2 and shown that it has been the target of selection during recent human evolution 4,5,6. In dyslexia,
we have completed a full genome scan using a quantitative trait loci (QTL) strategy and replicated
linkages on chromosome 6p, 2p and 186,7. For specific language impairment, QTL linkage analysis has
highlighted a region on chromosome 19q with measures of expressive language and a region on
chromosome 16q with the non-word repetition test and reading measures9,10.
Chromosome regions implicated by family studies in autism, specific language impairment and dyslexia
have been replicated in independent families. For all significant and replicated linkages, the region
containing the susceptibility gene(s) are being narrowed by family based association studies. Candidate
genes in the critical region are tested for etiologic mutations or variants that are potentially involved in
susceptibility to these childhood developmental disorders. Recently, using this approach we have
identified a strong association with dyslexia for a candidate gene, KIAA0319, on chromosome 6p22 with a
possible function in cell adhesion and neuronal migration11,12. Our goal is for a molecular understanding of
the neurodevelopmental pathways, which should enable better diagnosis and potential treatments.
1. The International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome
7q. Hum Molec Genet 1998; 7:571-578.
2. The International Molecular Genetic Study of Autism Consortium. Further characterisation of the autism susceptibility locus AUTS1 on chromosome 7q.
Hum Molec Genet 2001; 10:973-982.
3. The International Molecular Genetic Study of Autism Consortium. A genome wide screen for autism; Strong evidence for linkage to chromosomes 2q, 7q
and 16p. Am J Hum Genet 2001; 69:570-581.
4. Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME. Localisation of a gene implicated in a severe speech and language disorder. Nature
Genet 1998; 18:168-170.
5. Lai C, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A novel forkhead-domain gene is mutated in a severe speech and language disorder.Nature
2001; 413: 519-523.
6. Enard W, Przeworski M, Fisher SE, Lai CSL, Wiebe V, Kitano T, Monaco AP, Pääbo S. Molecular evolution of FOXP2, a gene involved in speech and
language. Nature 2002; 418:869-872.
7. Fisher SE, Marlow AJ, Lamb J, et al. A quantitative trait locus on chromosome 6p influences different aspects of developmental dyslexia. Am J Hum Genet
1999; 64:146-156.
8. Fisher* SE, Francks* C, Marlow AJ, MacPhie IL, Williams DF, Cardon LR, Ishikawa-Brush Y, Richardson AJ, Talcott JB, Gayan J, Olson RK, Pennington BF,
Smith SD, DeFries JC, Stein JF and Monaco AP. Independent genome-wide scans in identify a chromosome 18 quantitative-trait locus influencing dyslexia.
Nature Genetics 2002; 30:86-91.
9. The Specific Language Impairment Consortium. A genome-wide scan identifies two novel loci involved in Specific Language Impairment (SLI). Am J Hum
Genet 2002; 70:384-398.
10. The Specific Language Impairment Consortium Highly significant linkage to SLI1 locus in an expanded sample of individuals affected by Specific
Language Impairment (SLI). Am J Hum Genet 2004; 74:1225-1238.
11. Francks* C, Paracchini* S, Smith SD, Richardson AJ, Scerri TS, Cardon LR, Marlow AJ, MacPhie IL, Walter J, Pennington BF, Fisher SE, Olson RK,
DeFries JC, Stein JF, Monaco AP. A 77 kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the UK and USA. Am J Hum Genet
2004; 75:1046-1058.
12. Paracchini S, Thomas A, Castro S, Lai C, Paramasivam M, Wang Y, Keating BJ, Taylor JM, Hacking DF, Scerri T, Francks C, Richardson AJ, Wade-Martins
R, Stein JF, Knight J, Copp AJ, LoTurco J, Monaco AP. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a
novel gene involved in neuronal migration. Hum Molec Genet 2006; 15(10):1659-66.