Genetic studies on a multiplex Autism family in Hong Kong

Dr Chung, Brian Hon Yin   (Principal Investigator (PI))

Dr Fung Cheuk Wing   (Co-Investigator)

Professor Wong Chun Nei Virginia   (Co-Investigator)

Professor Yang Wanling   (Co-Investigator)

24

2009-01-01

65402

Genetic studies on a multiplex Autism family in Hong Kong

autism, CNVs, genetic studies, multiplex family, SNPs

Genetic Disease,Paediatrics

200807176079

Small Project Funding

2008

Completed

Autism is the most common neuro-developmental disorder and classically consists of the triad of impairments in social interaction, communication and repetitive stereotypic behaviors. It is heterogeneous and there is a continuum of related disorders, i.e. Autism Spectrum Disorders (ASD). It is estimated to affect 15-20 in 10,000 children, while all ASDs combined affect about 60 in 10,000 children. Study in Hong Kong showed that it has a prevalence of 16.1 per 10,000 children under 15 years old [1]. Autism is a disease with strong genetic component. Twin studies show a concordance of 60-92% for monozygotic twins and 0-10% for dizygotic pairs, depending on phenotypic definitions [2-4]. Despite a strong genetic load, the search for mutations and susceptibility genes for autism has generated mixed and sometimes controversial results. This could be caused by two reasons: one is that the disease may be caused by a combination of many common genetic variations and each with a small contribution to the disease susceptibility, or rare mutations with high penetrance but affecting only small number of families. Secondly, there is probably a strong phenotypic heterogeneity for the disease that confounds the effort in finding the genetic factors involved in the disease. Subpopulation stratification and the possibility that certain genes affecting the disease etiology in one population but not the other could also affect study results. To overcome these obstacles, dramatically increased sample size in an association study or a linkage study using affected sibpairs is essential, although it is often difficult to do. Alternatively, single families of big enough size with multiple affected individuals can be used for linkage studies, thus drastically reduce the possibility of both genetic and phenotypic heterogeneity. For example, it has been reported that a 2-base-pair in Neuroligin 4 gene (NLGN4) in Xp22.33 is responsible for X-linked mental retardation and autism[5], demonstrating the possibility that a complex disease like Autism could be caused by high penetrating mutations in certain families. We have identified a family with 4 affected individuals in Hong Kong that showed a strong indication in both disease homogeneity and involvement of a strong shared genetic factor(s) involved. All the 4 patients are boys and they meet the DSM-IV criteria for autism. Clinical assessment did not reveal any obvious features suggestive of known genetic disorders associated with autism. See attachment for a diagram showing the pedigree and significance of the research proposal References 1. Wong VCN et al. Epidemiological study of autism spectrum disorder in China. J Child Neurol 2008, 23(1): 67-72. 2. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 2008, 9:341-355. 3. Gupta AR, State MW. Recent advances in the genetics of autism. Biol Psychiatry 2007, 61:429-437. 4. Muhle R et al. The genetics of autism. Pediatrics 2004, 113:e472-486. 5. Laumonnier F, et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 2004, 74:552-557.