Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Low-grade parental gonosomal mosaicism in CHD2 siblings with Smith-Magenis-like syndrome.

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.

Long-read sequencing reveals chromothripsis in a molecularly unsolved case of Cornelia de Lange syndrome.

Thanks to a long-read sequencing (LRS) approach, in this study, we have reported a molecularly solved case of a proband with a clinical diagnosis of Cornelia de Lange syndrome (CDLS), which is a multisystemic disorder whose causative molecular defects involve cohesin complex genes, with NIPBL located at 5p13.2 accounting for approximately 50%-60% of CDLS cases. The first-tier tests revealed an abnormal karyotype 46,XY,t(5;15)(p13;q25)dn and a preserved NIPBL sequencing. Copy number variants (CNVs) at the translocation breakpoints, in disease genes, or in probably pathogenic loci were excluded by a-CGH analysis. Through fluorescence in situ hybridization (FISH) analysis on derivative chromosome 5, the breakpoint was relocated 3 Mb far from NIPBL 5'UTR, which seemed fully maintained as FISH-probe mapping to the gene showed no split signals. Moreover, tri-color FISH revealed an apparently balanced paracentric inversion including NIPBL on derivative 5. Based on the strong clinical suspicion, we evaluated the NIPBL transcript by RT-qPCR that revealed a normal amount of transcript till exon 22 and a halved amount of the transcript from exon 23 to 3'UTR, indicating the expression of a truncated transcript probably leading to a defective protein. Despite RT-qPCR confirmed the patient's CDLS clinical diagnosis, the molecular mechanism underlying this event remained to be an unsolved challenge for years. The LRS approach with nanopore technologies was able to fill the gap in this complex scenario and highlighted a chromothripsis event marked out at 5p13.2 by 36 breaks clustered in a 7.3-Mb region. The NIPBL gene was disrupted by 16 breaks and the resulting fragments were relocated in different positions and orientations. LRS confirmed the previous findings, and it has been proven to be crucial to define the complex chromosomal rearrangement in this patient which escaped current diagnostic investigations. Its application in the clinical practice will contribute to solve the unsolved.