title: Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus.
abstract: Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown to simultaneously cause TAAD and patent ductus arteriosus (PDA). We identified two large Dutch families with TAAD/PDA and detected two different novel heterozygote MYH11 variants in the probands. These variants, a heterozygote missense variant and a heterozygote in-frame deletion, were predicted to have damaging effects on protein structure and function. However, these novel alterations did not segregate with the TAAD/PDA in 3 out of 11 cases in family TAAD01 and in 2 out of 6 cases of family TAAD02. No mutation was detected in other known TAAD genes. Thus, it is expected that within these families other genetic factors contribute to the disease either by themselves or by interacting with the MYH11 variants. Such an oligogenic model for TAAD would explain the variable onset and progression of the disorder and its reduced penetrance in general. We conclude that in familial TAAD/PDA with an MYH11 variant in the index case caution should be exercised upon counseling family members. Specialized surveillance should still be offered to the non-carriers to prevent catastrophic aortic dissections or ruptures. Furthermore, our study underscores that segregation analysis remains very important in clinical genetics. Prediction programs and mutation evaluation algorithms need to be interpreted with caution.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.forename: Jasper
authors.initials: J
authors.lastname: van der Smagt
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.forename: Ruben
authors.initials: R
authors.lastname: Van't Slot
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Jelena
authors.initials: J
authors.lastname: Medic
authors.forename: Irene
authors.initials: I
authors.lastname: Joziasse
authors.forename: Jaap
authors.initials: J
authors.lastname: Deckers
authors.forename: Jolien W
authors.initials: JW
authors.lastname: Roos-Hesselink
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.forename: Hubert F
authors.initials: HF
authors.lastname: Baars
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Lisa
authors.initials: L
authors.lastname: Golmard
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Annette F
authors.initials: AF
authors.lastname: Baas
mesh_terms: D000328:Adult; D000368:Aged; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002874:Chromosome Mapping; D020090:Chromosome Segregation / Q000235:genetics*; D004374:Ductus Arteriosus, Patent / Q000235:genetics* / Q000473:pathology; D005260:Female; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C509903:MYH11 protein, human; D018995:Myosin Heavy Chains