ABSTRACT
Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal-dominant inherited disorder characterised by multiple gastrointestinal hamartomatous polyps, melanin spots of the oral mucosa and digits, and an increased risk for various neoplasms. The PJS results from germline alterations of the STK11/LKB1 tumour suppressor gene, located on 19p13.3, and encoding a serine/threonine kinase. The detection of STK11 germline mutations, in only 50-70% of PJS families, has suggested a genetic heterogeneity of the disease. We report the case of a family with typical features of PJS, including gastrointestinal hamartomatous, breast cancers and melanin spots of the oral mucosa. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) of the 19p13 region allowed us to identify an approximately 250 kb heterozygous deletion removing entirely the STK11 locus. This report, which constitutes the first description of a complete germline deletion of STK11, shows that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.
Subject(s)
Gene Deletion , Peutz-Jeghers Syndrome/genetics , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinase Kinases , Adolescent , Adult , Chromosomes, Human, Pair 19/genetics , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Exons/genetics , Family Health , Female , Germ-Line Mutation , Humans , In Situ Hybridization, Fluorescence , Male , Microsatellite Repeats , Middle Aged , Neurofibromatosis 1/genetics , Neurofibromatosis 1/pathology , Peutz-Jeghers Syndrome/pathology , Polymerase Chain Reaction/methodsABSTRACT
A couple was referred for exploration of repetitive abortions. The man was found to be a carrier of a balanced reciprocal translocation t(9;10)(q11;p11.1). The meiotic segregation of chromosomes 9 and 10 was analysed in 5,157 spermatozoa from this translocation carrier and in 15,255 spermatozoa from three control donors using three-colour fluorescence in situ hybridisation (FISH). The theoretical viability of the different segregation patterns was performed using the computer system HC Forum developed by the Department of Cytogenetics at the Grenoble University Medical School, La Tronche, France. A normal or balanced constitution was found in 56.25% of the analysed spermatozoa. The tertiary 3:1 segregation mode was the most frequently observed (14.37%). The frequencies of adjacent-1, adjacent-2 and 3:1 interchange modes were 12.85, 9.38 and 7.14% respectively. The cumulative frequency of non-viable imbalance was estimated at 20.91% according to the theorical viability of the different segregation patterns. Spermatozoa aneuploidy frequency was also evaluated for chromosomes X, Y and 18, and there was no evidence of interchromosomal effect in spermatozoa from the translocation carrier. FISH analysis of spermatozoa in combination with the viability theorical estimation of the different segregation patterns could be considered a useful tool for genetic counselling in carriers of reciprocal translocation.
