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A novel pericentric inversion of chromosome 3 cosegregates with a developmental-behavioural phenotype
  1. D Efron1,2,3,
  2. M B Delatycki2,3,4,5,6,
  3. M G de Silva2,5,
  4. A Langbein7,
  5. W Slaghuis7,
  6. A Larson8,
  7. H-H M Dahl2,3,5,
  8. S M Forrest2,3,5
  1. 1Centre for Community Child Health, Royal Children’s Hospital, Parkville, Victoria, Australia
  2. 2Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
  3. 3Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
  4. 4Genetic Health Services Victoria, Royal Children’s Hospital, Parkville, Victoria, Australia
  5. 5Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Parkville, Victoria, Australia
  6. 6Department of Paediatrics, Monash University, Clayton, Victoria, Australia
  7. 7Department of Psychology, University of Tasmania, Sandy Bay, Tasmania, Australia
  8. 8Calvary Rehabilitation Service, New Town, Tasmania, Australia
  1. Correspondence to:
 Dr M B Delatycki, Genetic Health Services Victoria, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia;
 delatycm{at}cryptic.rch.unimelb.edu.au

https://doi.org/10.1136/jmg.40.2.e15

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    Current advances in genetic knowledge and analysis have facilitated the shift in emphasis from single gene disorders to complex traits such as cancer and atopic disorders where changes in more than one gene usually contribute to the disease phenotype. A challenging area of complex trait research is the determination of the genetic basis of behavioural phenotypes. Early studies in this area focused on classical linkage analysis in pedigrees which segregated the trait of interest and led to the identification of genes for intellectual disability, such as fraX(A).1,2 In this disorder, mutations in a single gene are sufficient to generate the disease phenotype.

    In contrast, with other neurodevelopmental disorders, results to date have been much more complex. With ADHD, for example, a large number of genes affecting neurotransmitter function, particularly dopamine, have been implicated. However, results from linkage or association studies have not been reliably replicated. Even the most promising gene candidates are implicated in only a small percentage of ADHD cases.3,4 Identification of the genes involved is a challenging task. Firstly, accurate phenotype definition is crucial to successful outcomes in these pooled studies. Secondly, neurodevelopmental disorders such as ADHD are multifactorial, with a number of different genes, likely to be of varying effect and interacting with environmental influences, presumably contributing to the development of the observed phenotypes.

    We have identified an extended family where the proband, a child with moderate intellectual disability as well as severe conduct disturbance, was found to have a pericentric inversion of chromosome 3. The inversion was found to cosegregate with developmental-behavioural problems in other members of the family. In order to describe the phenotype, a developmental-behavioural paediatrician undertook a standardised clinical evaluation of eight of the juvenile members of the extended family. The findings are presented in this paper.

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