Mutations Screening For Peutz-Jeghers Syndrome And Marfan Syndrome

Monogenic disease is controlled by a pair of alleles and characterized as Mendelianinheritance. It is a natural model to study the relationship between disease and gene. Thereare lots of monogenic diseases that threatened to human health. It is necessary to excavatethe genetic disease resources and carry out the relevant study.Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder, whichis characterized by mucocutaneous pigmentation and hamartomatous polyps of thegastrointestinal tract. STK11gene (serine/threonine kinase11) located at chromosomeregion19p13.3is the disease-causing gene for PJS. Mutations of STK11gene have beenfound in most of PJS patients. Because PJS patients are more susceptible to cancerscompared to healthy people, it is significant to make early diagnose and therapy for PJSpatients.Marfan syndrome (MFS) is an autosomal dominant disease involving skeleton, eye,cardiovascular and other systems. The typical clinical manifestations are increased height,disproportionately long limbs and digits, subluxation of the lenses and aortic aneurysm.FBN1gene (fibrillin1) is the disease gene for MFS. MFS patients are prone to developcardiovascular system complications such as aortic dissection or rupture of aortic aneurysmthat are life threatening. So it is necessary to make early diagnosis for MFS patients.Seven PJS families and two MFS families from southwest region of China wereenrolled in our study. Family investigation and pedigree analysis were performed andmutations of STK11/FBN1were screened. Our results enlarged the spectrums of PJS/MFSand provided clues to combine the relationships between phenotype and genotype.Part1: Mutation screening for STK11gene in Peutz–Jeghers syndrome familiesand sporadic casesMethod: After family investigation and pedigree analysis in seven PJS probands,clinical data were collected. Blood samples of probands, family members and100healthy controls were obtained and genomic DNA was extracted. The whole coding regions andexon-intron boundaries of STK11gene were screened by polymerase chain reaction anddirect sequencing.Results:1. The clinical features for seven probands were characterized by obviousmucocutaneous pigmentation and multiple polyps of the gastrointestinal tract. Probands1-4had positive family history.2. Six mutations of STK11gene were indentified in seven PJS probands (mutationrate:85.7%). There were four point mutations (c.180C>G, c.526G>A, c.1062C>G andc.1088C>T) and two insertions (c.805ins G and c.843ins C), which caused thecorresponding amino acid changes and translation termination. However, these mutationswere not found among healthy family members and100healthy controls. Three mutationsincluding c.1088C>T, c.805ins G and c.843ins C were firstly found in PJS patients.3. According to clinical features, results of gastroscope and enteroscope, pathologicalcharacteristics，family history and mutation detection of STK11gene, seven probands couldbe clearly diagnosed as PJS.Part2: Mutation screening for FBN1gene in two families with Marfan syndromeMethod: Family investigation and pedigree analysis were performed, and clinical datawere collected in two PJS families. Blood samples including probands, family members and100healthy controls were obtained and genomic DNA was extracted. Mutation of FBN1gene was performed by polymerase chain reaction and direct sequencing.Results:1. These two families were characterized as an autosomal dominant inheritance. Theclinical manifestations for two probands were increased height, disproportionately longlimbs and digits. Cardiac ultrasound examination pointed out sinus of valsalva (or aorta)become wide and with aortic insufficiency.2. Results of mutation detection demonstrated that the same mutation of FBN1gene,a G-to-A substitution in exon27was identified in these two families (c.3463G>A), whichresulted in amino acid change from Asp to Asn at1155(p. Asp1155Asn). However, thismutation was absent in healthy family members and100healthy controls. This mutationwas firstly reported in Chinese Han population with Marfan syndrome. 3. According to the revised Ghent criterion, with clinical features, family history,cardiac ultrasound examination and mutation detection for FBN1gene, the two probands oftwo families could be diagnosed as MFS.