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While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1 , which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.

Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology.

Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as reduced or incomplete penetrance. Variable and incomplete penetrance may explain why inherited diseases are occasionally transmitted through unaffected parents, but also why clinically healthy individuals can carry potentially pathogenic variants without expressing features of the disease. Here, we will provide an overview of factors that play a fundamental role in the concept of penetrance and expressivity of cancer predisposing genes in children with malignancies. These findings are important to understand the complexity of inherited diseases and cancer development and to improve genetic counselling for the affected families., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer., Conclusions: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology. What is Known: • A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). What is New: • Knowing about an underlying CPS and, thus, the risk of recurrence in other children is of great interest to affected families.