Pathogenic variants within the CREBBP and EP300 genes account for the majority of individuals with Rubinstein-Taybi syndrome (RSTS). Data are presented from a large cohort of 395 individuals referred for diagnostic testing of CREBBP, and of the 19 CREBBP missense variants classified as likely pathogenic in this study, 17 were within the histone acetyltransferase (HAT) domain, providing evidence that this domain is critical to the normal function of the CREBBP protein (CBP). The data presented here, combined with other published results, suggest that the presence of a missense variant within the CBP HAT domain can be considered as moderate evidence of pathogenicity in the context of official variant interpretation guidelines. Within our study cohort, 129 had a pathogenic or likely pathogenic CREBBP variant and 5 had a variant of uncertain significance (VUS) which warranted familial studies. 147 of the remaining probands were also screened for EP300 and a further 16 pathogenic or likely pathogenic variants were identified, plus one VUS. Therefore, this analysis has provided a molecular diagnosis in at least 145 individuals with RSTS (37%) and identified a wide range of variants (n = 133) of which 103 were novel.

Transcription of SHOX is dependent upon the interaction of the gene with a complex array of flanking regulatory elements. Duplications that contain flanking regulatory elements but not the SHOX gene have been reported in individuals with SHOX haploinsufficiency syndromes, suggesting that alterations to the physical organisation or genomic architecture may affect SHOX transcription. Individuals with tall stature and an additional X or Y chromosome have an extra copy of both the SHOX gene and the entire SHOX regulatory region, so all three copies of SHOX can be expressed fully. However, for a duplication of the SHOX gene that does not include all of the flanking regulatory elements, the potential effect on SHOX expression is difficult to predict. We present nine unpublished individuals with a SHOX whole gene duplication in whom the duplication contains variable amounts of the SHOX regulatory region, and we review 29 similar cases from the literature where phenotypic data were clearly stated. While tall stature was present in a proportion of these cases, we present evidence that SHOX whole gene duplications can also result in a phenotype more typically associated with SHOX haploinsufficiency and are significantly over-represented in Leri-Weill Dyschondrosteosis and idiopathic short stature probands compared to population controls. Although similar-looking duplications do not always produce a consistent phenotype, there may be potential genotype-phenotype correlations regarding the duplication size, regulatory element content and the breakpoint proximity to the SHOX gene. Although ClinGen (clinicalgenome.org) do not currently consider SHOX whole gene duplications to be clinically significant, the ClinGen triplosensitivity score does not take into account the context of the duplication, and more is now known about SHOX duplications and the role of flanking elements in SHOX regulation. The evidence presented here suggest that these duplications should not be discounted without considering the extent of the duplication and the patient phenotype, and should be included on diagnostic laboratory reports as variants of uncertain significance. Given the uncertain pathogenicity of these duplications, any reports should encourage the exclusion of all other causes of short stature where possible.

Background Transcriptional regulation of the SHOX gene is highly complex. Much of our understanding has come from the study of copy number changes of conserved non-coding sequences both upstream and downstream of the gene. Downstream deletions have been frequently reported in patients with Leri–Weill dyschondrosteosis or idiopathic short stature. In contrast, there are only four cases in the literature of upstream deletions that remove regulatory elements. Although duplications flanking the SHOX gene have also been reported, their pathogenicity is more difficult to establish. To further evaluate the role of flanking copy number variants in SHOX-related disorders, we describe nine additional patients from a large SHOX diagnostic cohort. Results The nine cases presented here include five with duplications (two upstream of SHOX and three downstream), one with a downstream triplication and three with upstream deletions. Two of the deletions remove a single conserved non-coding element (CNE-3) while the third does not remove any known regulatory element but is just 4 kb upstream of SHOX, and the deleted region may be important in limb bud development. We also describe six families with novel sequence gains flanking SHOX. Three families had increased dosage of a proposed regulatory element approximately 380 kb downstream of SHOX (X:970,000), including one family with the first ever reported triplication of this region. One family had two in cis downstream duplications co-segregating with LWD, and the two others had a duplication of just the upstream SHOX regulatory element CNE-5. Conclusions This study further extends our knowledge of the range of variants that may potentially cause SHOX-related phenotypes and may aid in determining the clinical significance of similar variants.

Background: Approximately 1 in 1000 men have a 47,XYY karyotype. Previous publications have presented cases of infertile XYY men and have suggested that the additional Y chromosome may cause disrupted meiosis leading to sperm apoptosis. The purpose of the current study was to determine whether XYY men are over-represented in infertility cohorts.   Methods: In this paper, an ongoing infertility cohort was evaluated for Y chromosome microdeletions using the MLPA technique and the data from the first 2000 referrals were recorded. Moreover, the MLPA technique detected 47,XYY karyotypes. Results: Four XYY individuals were identified within the cohort. One of the four XYY men was shown to have an apparent gr/gr partial AZFc deletion on both Y chromosomes while Sertoli cell only syndrome was detected in another case. The other two cases (out of 2000) might, therefore, represent an incidental finding.  Conclusion: The gr/gr deletion is not detectable by the multiplex PCR method; therefore, there might be additional explanations for the fertility problems of infertile XYY men reported in previously published articles. It seems that among other cases, their XYY karyotype may be coincidental, rather than causative of their fertility issues.