Genotype–phenotype specificity in Menke–Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP

Abstract

CREBBP loss-of function variants cause Rubinstein-Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant.Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype-phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder "Menke-Hennekam syndrome" to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research. K E Y W O R D SMenke-Hennekam syndrome, Rubinstein-Taybi syndrome, CREBBP

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome

“…CREBBP is another gene associated with transcription co‐activation following chromatin remodeling. This individual has a variant in one of the final two exons of CREBBP , consistent with the emerging Menke–Hennekam syndrome, a disorder clinically distinct from Rubinstein–Taybi syndrome (Angius et al, 2019; Banka et al, 2019; Menke et al, 2016). Finally, POGZ was observed in one individual who showed overlap with the previously described White‐Sutton syndrome, but with relatively mild cognitive involvement and lacking the characteristic behavioral and gastrointestinal manifestations (Stessman et al, 2016).…”

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome

“…Overall, this work emphasizes the possibility of undiscovered phenotypes linked with even well-studied genes. 39,40…”

The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin

“…The ability of the TAZ2 domain to bind DNA and change the substrate preferences of CBP to favour acetylation of H3K27 appears to further explain mechanistically how assembly of histones into chromatin modulates CBP activity and substrate selection (An and Roeder, 2003;Kraus et al, 1999). Moreover, the key role played by the TAZ2 domain in CBP function may also rationalize recent findings that missense mutations within TAZ2 expected to affect its structural integrity are associated with the rare developmental disorder Menke-Hennekam syndrome (MKHK) (Banka et al, 2019;Menke et al, 2018;Menke et al, 2016). Importantly, MKHK patients carrying mutations in key zinc-coordinating residues that are likely to destabilize the TAZ2 domain display a clinical phenotype that is distinct from patients with Rubinstein-Taybi syndrome (RSTS), which is caused by loss of CBP function (Hennekam, 2006;Menke et al, 2016).…”