CC-03
Unravelling the X Files: Challenges and Dilemmas
Isabel M. CarreiraI
ILaboratório de Citogenética e Genómica, Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal; CIMAGO – Centro de Investigação em Meio Ambiente, Genética e Oncobiologia, Coimbra, Portugal; CNC – Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal. E-mail: i_marques@hotmail.com
]]> Array-Comparative Genomic Hybridization (array-CGH) has increased the diagnostic yield in patients with intellectual disability (ID), autism spectrum disorders and multiple congenital anomalies due to its improved resolution. X-chromosome has been focus of attention due to the bias in the affected maleto-female ratio and to the knowledge of X-linked genes associated with ID. With array-CGH we can either detect single gene imbalances, chromosomal region imbalances and even aneuploidies.
In a cohort of 1000 patients studied by Agilent 180K oligonucleotide array-CGH several X-chromosome imbalances were detected. Single gene deletions involving ZNF41 or IL1RAPL1 genes were equitably observed in 8 patients; DMD imbalances in 3 females and SHOX gene duplications in 1 female and 9 males. An intragenic deletion in SLC9A6 gene associated with Christianson syndrome that segregated in the family was also detected.
In 6 patients we identified Xp22.31 duplications, 3 females, 1 male with maternal inheritance and 2 males whose inheritance was not yet determined. A chromosome Xq27.1q28 interstitial duplications in 2 males, 1 maternally inherited and the other not yet determined were also identified. We also found other genomic imbalances but in single cases as for example a complex rearrangement with multiple imbalances at Xp22.33p22.2 in a male patient, maternally inherited; an Xp11.3p11.23 duplication in a female with ID whose mother is also affected and a case of triple X in an autistic female.
The challenge with X-chromosome imbalances is to, understand the biological mechanism(s) behind, interpret their impact on the phenotype, due to the presence of some alterations in the normal population and to X-chromosome inactivation in females. Clinical laboratory reporting has to use the correct nomenclature and a clear and objective interpretation of the results.
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