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Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

The prokineticin-2 (PROK2) is a small peptide belonging to the prokineticin family. In humans and rodents this chemokine is primarily involved in the control of central and peripheral reproductive processes. Klinefelter's syndrome (KS) is the first cause of male genetic infertility, due to an extra X chromosome, which may occur with a classical karyotype (47, XXY) or mosaic forms (46, XY/47, XXY). In affected subjects, pubertal maturation usually begins at an adequate chronological age, but when development is almost complete, they display a primary gonadal failure, with early spermatogenesis damage, and later onset of testosterone insufficiency. Thus, the main aim of the present study was to investigate the serum levels of PROK2 in prepubertal and adult KS patients, comparing them with healthy subjects. We showed for the first time the presence of PROK2 in the children serum but with significant changes in KS individuals. Indeed, compared with healthy subjects characterized by PROK2 serum elevation during the growth, KS individuals showed constant serum levels during the sexual maturation phase (higher during the prepubertal phase but lower during the adult age). In conclusion, these data indicate that in KS individuals PROK2 may be considered a biomarker for investigating the SK infertility process. Key words: Klinefelter syndrome, prepubertal, adults, prokineticin-2, infertility. La procineticine 2 (PROK2) est un petit peptide faisant partie de la famille des procineticines. Chez l'humain et les rongeurs, cette chimiokine joue principalement un role dans le controle central et peripherique des processus de la reproduction. Le syndrome de Klinefelter (SK) constitue la principale cause d'infertilite masculine de nature genetique en raison d'un chromosome X supplementaire, ce qui peut survenir avec un caryotype classique (47, XXY) ou des formes mosarques (46, XY/47, XXY). Chez les sujets atteints, le passage a la puberte commence habituellement a un age chronologique adequat, mais lorsque le developpement est presque termine, ils presentent une insuffisance gonadique primitive, avec des dommages de la spermatogenese precoces et une insuffisance de testosterone d'apparition plus tardive. Par consequent, la presente etude portait avant tout sur la comparaison des taux seriques de PROK2 entre des patients atteints de SK en prepuberte ou a l'age adulte et des sujets en bonne sante. Nous avons montre pour la premiere fois la presence de PROK2 dans le serum des enfants, mais avec des modifications importantes chez les personnes atteintes du SK. De fait, comparativement aux sujets en bonne sante caracterises par une hausse des taux seriques de PROK2 au cours de la croissance, les personnes atteintes du SK presentaient une augmentation des taux seriques de maniere constante au cours de la phase de maturation sexuelle (plus elevee au cours de la phase prepubere, mais moins elevee a l'age adulte). En conclusion, ces donnees montrent que l chez les personnes atteintes de SK, es taux de PROK2 pourraient etre consideres comme etant des biomarqueurs permettant d'etudier le processus d'infertilite dans le SK. [Traduit par la Redaction] Mots-cles: syndrome de Klinefelter, prepuberte, adultes, procineticine 2, infertilite., Introduction The chemokine prokineticin-2 (PROK2) is a small peptide belonging to the prokinetidn family. The preokineticins (PROK1 and PROK2) and their receptors (PKR1 and PKR2) are widely distributed in the [...]

Objective High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs. Design and Methods In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed. Results The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction. Conclusion The increase in the number of extra-Xs is associated with a "dose-dependent" progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance. [ABSTRACT FROM AUTHOR]

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15–40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2–37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed. [ABSTRACT FROM AUTHOR]

To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries. [ABSTRACT FROM AUTHOR]

Background: A peculiar subgroup of patients with partial or complete atrioventricular canal defect exhibits a spectrum of left‐sided obstructions including right ventricular dominance and aortic coarctation. The association of atrioventricular canal defect with left‐sided obstructions is found in several genetic syndromes; however, the molecular basis of nonsyndromic atrioventricular canal defect with aortic coarctation is still poorly understood. Although some candidate genes for nonsyndromic atrioventricular canal defect are known, a complex oligogenic inheritance determined in some cases by the co‐occurrence of multiple variants has also been hypothesized. Case Report: We describe a nonsyndromic infant with mesocardia with viscero‐atrial situs solitus, partial atrioventricular canal defect, mild right ventricular dominance, and coarctation of the aorta. Next generation sequencing genetic testing revealed variants in two genes, GDF1 and NOTCH1, previously reported in association with atrioventricular canal defect and left‐sided obstructive lesions, respectively. Conclusion: The present report could support the hypothesis that the co‐occurrence of cumulative variants may be considered as genetic predisposing risk factor for specific congenital heart defects. [ABSTRACT FROM AUTHOR]

Background. The 22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition at high risk of developing both psychosis and motor disorders. Social Cognition (SC) deficits have been associated not only with schizophrenia but also with Parkinson's disease (PD). The present study assessed SC deficits in 22q11.2DS and investigated the interaction between motor symptoms and deficits in Facial Emotion Expressions (FEE) recognition and in Theory of Mind (ToM) tasks in people with 22q11.2DS. Methods. We recruited 38 individuals with 22q11.2DS without psychosis (N = 38 , DEL) and 18 with 22q11.2DS and psychosis (N = 18 , DEL_SCZ). The Positive And Negative Syndrome Scale (PANSS), Ekman's 60 Faces Test (EK-60F), the Awareness of Social Inference Test (TASIT EmRec), and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (UPDRS III) were administered. Correlations were sought between UPDRS III and both TASIT EmRec and EK-60F scores. Analyses were conducted separately for each psychopathological subgroup. Results. Higher UPDRS III (p = 0.04) and lower EK-60F (p = 0.025) scores were observed in the DEL_SCZ group. We found inverse correlations between UPDRS III and both TASIT EmRec (r = − 0.289 , p = 0.031) and EK-60F (r = − 0.387 , p = 0.006) scores in the whole sample. Correlations were no longer significant in the DEL_SCZ group (UPDRS III-TASIT EmRec p = 0.629 ; UPDRS III-EK60F p = 0.933) whilst being stronger in the DEL group (TASIT EmRec, r = − 0.560 , p < 0.001 ; EK60F, r = − 0.542 , p < 0.001). Analyses were adjusted for CPZ Eq and IQ. Conclusions. A modulation between FEE recognition deficits and motor symptoms and signs was observed in the 22q11.2DS group, likely affecting patients' quality of life. [ABSTRACT FROM AUTHOR]