TY - JOUR
T1 - CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype
AU - Menke, Leonie A.
AU - van Belzen, Martine J.
AU - Alders, Marielle
AU - Cristofoli, Francesca
AU - Ehmke, Nadja
AU - Fergelot, Patricia
AU - Foster, Alison
AU - Gerkes, Erica H.
AU - Hoffer, Mariette J. V.
AU - Horn, Denise
AU - Kant, Sarina G.
AU - Lacombe, Didier
AU - Leon, Eyby
AU - Maas, Saskia M.
AU - Melis, Daniela
AU - Muto, Valentina
AU - Park, Soo-Mi
AU - Peeters, Hilde
AU - Peters, Dorien J. M.
AU - Pfundt, Rolph
AU - van Ravenswaaij-Arts, Conny M. A.
AU - Tartaglia, Marco
AU - Hennekam, Raoul C. M.
AU - DDD Study
PY - 2016/10
Y1 - 2016/10
N2 - Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n=5), feeding problems (n=7) and impaired hearing (n=7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. (c) 2016 Wiley Periodicals, Inc.
AB - Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n=5), feeding problems (n=7) and impaired hearing (n=7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. (c) 2016 Wiley Periodicals, Inc.
KW - CREBBP
KW - exon 30
KW - exon 31
KW - whole exome sequencing
KW - intellectual disability
KW - Rubinstein-Taybi syndrome
KW - RSTS
KW - syndrome
KW - mutation
KW - clinical features
KW - case series
KW - genotype-phenotype correlation
KW - CBP
KW - SPECTRUM
KW - MISSENSE
KW - DISEASE
KW - DOMAIN
KW - ZZ
U2 - 10.1002/ajmg.a.37800
DO - 10.1002/ajmg.a.37800
M3 - Article
SN - 1552-4825
VL - 170
SP - 2681
EP - 2693
JO - American Journal of Medical Genetics. Part A
JF - American Journal of Medical Genetics. Part A
IS - 10
ER -