Loss-of-function variants in CREBBP or EP300 result in Rubinstein-Taybi syndrome (RSTS). The previously reported cluster of variants in the last part of exon 30 and the beginning of exon 31 of CREBBP, overlapping with the ZNF2 (zinc finger, ZZ-type; residues 1701 to 1744) and ZNF3 (zinc finger, TAZ-type; residues 1764 to 1853) domains, is associated with atypical RSTS. The main features include developmental delay, short stature, microcephaly, distinctive facial features, autistic behavior, feeding difficulties, recurrent upper airway infections, and hearing impairment. Here, we report a 2-year-7-month-old Chinese girl presenting mild cognitive impairments, developmental delay, short stature, recurrent upper airway infections, and facial dysmorphism that resembled the phenotypes of previously reported atypical RSTS patients. The characteristic facial and limb dysmorphism for RSTS was absent in our patient. In addition, our patient exhibited novel phenotypes including attention deficit hyperactivity disorder (ADHD), sleep problem, and abnormal walking posture. Whole-exome sequencing (WES) identified a novel de novo in-frame deletion variant in the beginning of exon 30 of CREBBP (NM_004380:c.4897_4899delTTC, p.Phe1633del) in the HAT domain where no pathogenic variants have been previously reported to be responsible for atypical RSTS. Our case allows us to more accurately define the borders of the CREBBP coding sequence resulting in atypical RSTS, which are extended to the beginning of exon 30 (residue 1633) at the 5' end of CREBBP in the HAT domain, and reveals novel phenotypes observed in our atypical Chinese RSTS patient.
Keywords: CREBBP; Exon 30; Exon 31; HAT domain; Rubinstein–Taybi syndrome.