Purpose This study aimed to expand the clinical and biological understanding of POT1 tumor predisposition syndrome and raise awareness of its broad tumor spectrum and association with ultralong telomeres. Methods We conducted a retrospective analysis of 44 individuals carrying pathogenic or likely pathogenic POT1 variants identified between 2018 and 2025. Clinical, pathologic, and demographic data were extracted from medical records. Telomere length was assessed using in-gel hybridization of telomeric restriction fragments. Results Of 44 heterozygotes, 31 had the c.233T>C; p.(Ile78Thr) variant, 8 had c.1672dup; p.(Tyr558Leufs∗6), and 5 had other frameshifting, likely loss-of-function variants. Cancer was diagnosed in 27 heterozygotes (61%), totaling 84 primary malignancies (range: 0-8 per person), with most cases (79%) occurring after the age of 50 years. Melanoma (34%) and breast cancer in females (45%) were the most common. Additional tumors included papillary thyroid carcinoma, desmoid tumors, and diverse malignant and benign neoplasms. Colonic polyps were frequent. POT1 heterozygotes with the p.(Ile78Thr) variant exhibited significantly longer telomeres than control participants, with a 62-year-old woman showing comparable or even longer telomeres than her children. Conclusion POT1 pathogenic variants confer susceptibility to a wide tumor spectrum, notably melanoma and, unexpectedly, breast cancer. At least some of these variants are linked to ultralong telomeres, consistent with findings from this study and others. These findings support incorporating POT1 into multigene panels and suggest telomere length as a potential biomarker for diagnosis.

Glucose transport rate as assessed with the 3-O-Methyl-glucose method was significantly increased in adipocytes preincubated with aliphatic carboxylic acids. The magnitude of stimulation apparently depended on the chain length of the carboxylic acid, and was highest with palmitic acid (130 %). The stimulation was additive to the effect of insulin, and reflected a decrease of km rather than an increase in vmax of the transport rate. The results suggest that fatty acids may modulate the activity of the glucose transporter, providing an insulin-dependent supply of adipose tissue with glycerolphosphate during lipolysis for reesterification of excess fatty acids. Further, it is suggested that fatty acids mediate the stimulatory effect of catecholamines on glucose transport as observed in isolated fat cells.

Introduction: Data on patient satisfaction with the provision of genetic consultations using telemedicine are limited, especially those involving children. We compared patient satisfaction rates with telemedicine services versus traditional in-person encounters. Methods: A cross-sectional questionnaire-based study was conducted between January and June 2020. Questionnaires were distributed online to 1,672 consecutive patients who had received genetic counseling at our Genetics Institute in the clinical fields of adult and pediatric genetics, oncogenetics, and prenatal genetics, through in-person and/or telemedicine consultation. We used Likert scale with scores of 4-5 representing "satisfied"-"very satisfied" and 1-2 representing "very unsatisfied"-"unsatisfied." Results: The response rate was 27.3% (400 adults and 57 children <18 years), including 330 who had received in-person consultations (72.2%), 80 telemedicine consultations (17.5%), and 47 both consultations (10.3%). Mean satisfactory scores of 4-5 were reported by 82.1% in the in-person group versus 82.5% in the telemedicine group (p = 0.88). Mean scores of 1-2 were reported by 6.3% in the in-person group versus 11.2% in the telemedicine group (p = 0.31). No pediatric telemedicine group patient (n 12 = ) gave scores of 1-2 compared with 2/33 (6%) patients who had in-person pediatric consultations (p = 0.62). Most responders who had been counseled through telemedicine (n = 127, 84%) indicated willingness to use genetic services through telemedicine again. Conclusions: Users of genetic counseling through telemedicine, especially in the pediatric age group, were very satisfied at rates comparable to those of in-person consultations. Future research should evaluate patient compliance and views according to session type, information provided (e.g., diagnostic vs. negative results), and its nature (good vs. bad news).

Background: HNF1B deletion/intragenic mutations are the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) suggested by fetal ultrasound findings such as: parenchymal hyperechogenicity, overt cystic changes or gross morphological urinary system (UT) abnormalities. The postnatal evolution of these 17q12 deletions encompassing the HNF1B gene-associated findings has not been assessed in depth. Methods: In this observational study, we present postnatal follow-up findings in 5 of 6 cases (one pregnancy was terminated on parental request) of fetal-onset cystic/hyperechogenic kidneys eventually diagnosed with 17q12 microdeletion encompassing the HNF1B gene between 2009 and 2017. Results: Complete normalization of kidney parenchymal abnormalities and of depressed neonatal renal function was observed in 4/5 and 5/5 patients within 2-4.9 years and 1.5-8 months, respectively. All 5 patients had preserved normal renal function at 3-11 years of follow-up. The evolving later-onset renal features included: hypomagnesemia, hyperuricemia, urinary tract infection (UTI), and bilateral grade 3-4 vesicoureteral reflux and bladder diverticula in 3, 3, 2, and 1 patient, respectively. HNF1B gene deletion-associated extra-renal manifestations with delayed presentation were global developmental delay/autistic spectrum disorder (ASD), rolandic-type seizures, overweight, and borderline fasting hyperglycemia observed in 1-2 patients each. Family history was positive for small-size or asymptomatic cystic kidneys with normal function, diabetes mellitus, seizures, and mental/psychiatric problems in 3/6 cases. Conclusions: Fetal-onset HNF1B deletion-associated kidneys' parenchymal abnormalities confirmed postnatally with initially depressed renal function might undergo complete resolution within several years and few months, respectively. However, later-onset urinary tract, metabolic, and neurodevelopmental features of this mutation might appear over years. Therefore, genetic molecular evaluation/diagnosis and continuous follow-up for evolving features are mandatory in affected children.

OBJECTIVE:We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result.METHODS:During the study period (2014-2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis.RESULTS:A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5). Finally, in two fetuses of the same couple (Case #6), a compound heterozygous state was detected, consisting of the NPHP1 gene deletion and a sequence variant of uncertain significance. Two additional cases had normal WES results.CONCLUSION:Whole-exome sequencing may improve prenatal diagnosis in fetuses with CNS abnormalities.

In the presence of fetal structural abnormalities it is standard practice to perform chromosomal microarray (CMA). However, this can only explain 5-7% of the cases, and thus most cases are undiagnosed. Many of these cases may be due to gene mutations that cannot be detected by CMA. Due to the fact that such mutations occur in a large number of genes, it is not practical to perform gene-specific sequencing. The purpose of this study was to assess the added value of whole exome sequencing (WES) in fetuses with structural abnormalities, after a normal CMA result. When fetal structural abnormalities are detected we routinely perform CMA. Patients whose results are negative, are offered WES. During the study period (2015-2016) DNA extracted from amniocytes or from products of conception in 10 fetuses were subjected to WES. All except 2 cases were done in parallel with parental samples (trio) Patient clinical variables and WES findings are presented in Table 1. Seven fetuses had central nervous system (CNS) anomalies, of these 2 had additional non-CNS abnormalities. Four of these cases had a history of previous offspring with CNS malformations. A likely pathogenic variant was detected in 4 cases demonstrating CNS abnormalities (de novo COL1A1 mutation, homozygous VRK1 mutation, X-linked ARX mutation and, homozygous ERC2 mutation) and variant of uncertain significance (VUS) was detected in 2 cases (non-twins fetuses of the same couple - compound heterozygous NPHP1 mutation). Three additional fetuses, of them 2 with an isolated increased nuchal translucency (NT) and 1 with ambiguous genitalia and short long bones had normal WES results. Whole exome sequencing improves prenatal diagnosis in euploid fetuses with structural abnormalities, particularly those involving the CNS. In order to expedite interpretation of results, trio sequencing should be employed. The role of WES in fetuses with isolated increased NT necessitates further investigation.

ABSTRACTObjectiveA prenatal diagnosis of chromosome X short arm deletions may present a challenge in prenatal genetic counseling. We present clinical and molecular data of carriers of Xp distal deletions.MethodsWe assessed prenatal and postnatal phenotypes of individuals from three families with large Xp distal deletions and from a fourth family with a small Xp distal deletion. The work‐up included karyotyping, chromosomal microarray analysis, and assessment of the X inactivation pattern.ResultsFive out of eight women with large deletions had a short stature (<3rd percentile). Subjects from one family had developmental and emotional problems. All female carriers with small deletions had markedly short stature, whereas the men had mildly short stature. Chromosomal microarray analysis revealed 11.7‐19.3 Mb deletions in three families and a small ~1 Mb deletion in the fourth. The pseudoautosomal region 1 of the X chromosome was deleted in two families with large deletions. X inactivation was skewed in all tested cases with large deletions.ConclusionXp distal deletions are mainly associated with short stature. Skewing of the abnormal X chromosome may attenuate the phenotype in cases with large deletions. We suggest that prenatal evaluation in such cases should include sonographic follow‐up and assessment of the X inactivation pattern. © 2014 John Wiley & Sons, Ltd.