Abstract for presentation at 11th International Congress of Human Genetics

Homozygous R117H CFTR mutation - parental R117H or uniparental disomy or R117del?

  • Mrs Gemma Jenkins, The Children's Hospital at Westmead, NSW Australia, Australia
  • Dr Peter Cooper, The Children's Hospital at Westmead, NSW Australia, Australia
  • Dr Bruce Bennetts, Children's Hospital at Westmead, NSW Australia, Australia
  • Dr Elisabeth Dequeker, Department of Human Genetics, University of Leuven, Belgium

    • Cystic fibrosis (CF) is an autosomal recessive disease that predominantly affects the epithelia of the respiratory tract, exocrine pancreas, intestine, male genital tract and exocrine sweat glands. In some symptomatic individuals, only one or no mutation in the CFTR gene is detectable. While linkage analysis within the CFTR gene can help determining carrier status and prenatal testing, identification of the specific CFTR mutation is preferable.
    A 1 year old Caucasian girl was referred for molecular analysis of the CFTR gene, after presenting with failure to thrive and vomiting after meals. Her newborn CF screen was negative, and she had a paternal cousin with CF (genotype unknown). Testing by PCR-OLA (Celera Diagnostics) for 31 mutations and sequencing showed her to be homozygous for the R117H mutation in the CFTR gene. Follow-up screening of her parents by PCR-OLA revealed her father to be heterozygous for the R117H mutation and no mutations were detected in her mother. PCR-OLA testing of her symptomatic sibling did not identify any mutations. Microsatellite analysis for chromosome 7, including 3 intragenic CFTR markers excluded paternal isodisomy UPD7 and revealed a maternally derived deletion of at least exons 1 to 17 of the CFTR gene. Other chromosome 7 markers showed bi-parental inheritance. Further testing is planned to define the extent of the deletion and to determine if the entire gene and surrounding genes have been deleted. These microsatellite results also indicated that the proband’s sibling carried the deletion which would not have been picked up in a routine CF carrier screening program. Large deletions are not easily detected using most CF screening protocols. This case demonstrates the importance of familial studies to confirm any homozygous mutation by follow up screening of the parents. This result suggests that MLPA testing for deletions may be an important second tier of testing where a second CFTR mutation has not been identified.

    Conference Organiser - ICMS Pty Ltd