Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p < 0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75–86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55–59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD.

This work was supported by the Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: Ricerca Corrente [grant number RC2014/519-02] to M.M. and from ASM onlus 2010-2011 to M.M. The authors declare that they have no conflict of interest.

Background Chromothripsis, which is the local massive shattering of one or more chromosomes and their reassembly in a disordered array with frequent loss of some fragments, has been mainly reported in association with abnormal phenotypes. We report three unrelated healthy persons, two of which parenting a child with some degree of intellectual disability, carrying a chromothripsis involving respectively one, two, and three chromosomes, which was detected only after whole‐genome sequencing. Unexpectedly, in all three cases a fragment from one of the chromothripsed chromosomes resulted to be inserted within a nonchromothripsed one. Methods Conventional cytogenetic techniques, paired‐end whole‐genome sequencing, polymerase chain reaction, and Sanger sequencing were used to characterize complex rearrangements, copy‐number variations, and breakpoint sequences in all three families. Results In two families, one parent was carrier of a balanced chromothripsis causing in the index case a deletion and a noncontiguous duplication at 3q in case 1, and a t(6;14) translocation associated with interstitial 14q deletion in case 2. In the third family, an unbalanced chromothripsis involving chromosomes 6, 7, and 15 was inherited to the proband by the mosaic parent. In all three parents, the chromothripsis was concurrent with an insertional translocation of a portion of one of the chromothriptic chromosomes within a further chromosome that was not involved in the chromothripsis event. Conclusion Our findings show that (a) both simple and complex unbalanced rearrangements may result by the recombination of a cryptic parental balanced chromothripsis and that (b) insertional translocations are the spy of more complex rearrangements and not simply a three‐breakpoint event.

Background In the last few years trio‐whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition. Methods Trio‐WES was performed on a 4‐month‐old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections. Results WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short‐rib thoracic dysplasia. Conclusion The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants. The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.

Ludington and colleagues recently published an article in the American Journal of Medical Genetics Part A reporting a possible new microdeletion disorder involving the Contactin-Associated Protein 5 gene (CNTNAP5, OMIM *610519) (Ludington, Yu, Bae, & Barnett, 2020). The authors described a 9-year-old patient presenting with microcephaly, thin corpus callosum, and cognitive impairment. Array CGH identified a de novo 838 kb deletion at 2q14.3 involving CNTNAP5, which was deemed to be the cause of the child's phenotype. To date, this is the only reported case of a deletion solely involving CNTNAP5. Currently, five CNTNAP genes have been described, each encoding a Contactin-Associated Protein, a multidomain transmembrane structure predominantly found in the central and peripheral nervous sys