TY - JOUR
T1 - Autosomal dominant frontometaphyseal dysplasia
T2 - Delineation of the clinical phenotype
AU - Wade, Emma M.
AU - Jenkins, Zandra A.
AU - Daniel, Philip B.
AU - Morgan, Tim
AU - Addor, Marie C.
AU - Adés, Lesley C.
AU - Bertola, Debora
AU - Bohring, Axel
AU - Carter, Erin
AU - Cho, Tae Joon
AU - de Geus, Christa M.
AU - Duba, Hans Christoph
AU - Fletcher, Elaine
AU - Hadzsiev, Kinga
AU - Hennekam, Raoul C.M.
AU - Kim, Chong A.
AU - Krakow, Deborah
AU - Morava, Eva
AU - Neuhann, Teresa
AU - Sillence, David
AU - Superti-Furga, Andrea
AU - Veenstra-Knol, Hermine E.
AU - Wieczorek, Dagmar
AU - Wilson, Louise C.
AU - Markie, David M.
AU - Robertson, Stephen P.
N1 - Funding Information:
The authors would like to thank the participating families and J. Weissenbach for diagnostic expertise. The work was supported by funding from the Marsden Fund and Cure. Kids (S.P.R.). E.W. is supported by an Otago University postgraduate research scholarship. The authors declare no conflict of interest.
Funding Information:
The authors would like to thank the participating families and J. Weissenbach for diagnostic expertise. The work was supported by funding from the Marsden Fund and Cure Kids (S.P.R.). E.W. is supported by an Otago University postgraduate research scholarship.
Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2017/7
Y1 - 2017/7
N2 - Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
AB - Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
KW - Frontometaphyseal dysplasia
KW - TAB2
KW - TAK1
KW - keloid
KW - locus heterogeneity
KW - scoliosis
UR - http://www.scopus.com/inward/record.url?scp=85019126356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019126356&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38267
DO - 10.1002/ajmg.a.38267
M3 - Article
C2 - 28498505
AN - SCOPUS:85019126356
SN - 1552-4825
VL - 173
SP - 1739
EP - 1746
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 7
ER -