Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.

The relationship between vocabulary and grammar in two children with 5p deletion syndrome.

5p deletion syndrome is a rare genetic condition associated with severe speech and language problems. In general, research on speech and language skills is scarce, but there is more knowledge on phonetic and phonological skills than on lexical and grammatical skills. And till now no studies have addressed the relationship between grammar and vocabulary. Therefore, in this study, we address aspects of this relation based on longitudinal parent-reported data (MacArthur-Bates Communicative Development Inventories) from two children with this syndrome aged 2;0-7;3, and 1;11-7;1, respectively. We examine the development of the vocabulary size in each child, seen in relation to the development of grammar (inflections, combinations of words, complexity, and productivity), and see to what extent they can be compared to typically developing children. Results show that they follow a similar pattern to typically developing children but are delayed and have slightly different individual profiles.

Differences in DNA methylation status explain phenotypic variability in patients with 5p- syndrome.

Cri Du Chat syndrome, or 5p- syndrome, is characterized by a terminal or interstitial deletion on the short arm of chromosome 5 that causes variable clinical manifestations, including high-pitched cry in newborns, delayed growth, and global development. Different cytogenomic rearrangements, family history, and environmental factors may hinder the genotype-phenotype association. Thus, the phenotypic variability of this syndrome may not be limited only to variations in gene structure, such as deletions and duplications. It is possible that other mechanisms related to the activation or inactivation of promoters and/or exons of actively transcribed genes, such as DNA methylation are involved. Therefore, we studied the genome-wide methylation status profile of peripheral blood samples from fifteen patients with Cri du Chat Syndrome and nine control samples through the array method to look for Differentially Methylated Regions. We found that Differentially Methylated Regions outside the 5p region are mainly associated with regulating gene transcription, splicing, and chromatin remodeling. Most biological pathways are related to transcription, histone and chromatin binding, spliceosome and ribosomal complex, and RNA processing. Our results suggest that changes in the 5p region can cause an imbalance in other chromosomal regions capable of affecting gene modulation and thus explain the phenotypic differences in patients with 5p-.

Constitutional chromosomal anomalies in children, fetal alcohol syndrome, and maternal toxicant exposures: A longitudinal cohort study.

DNA alterations in gametes, which may occur either spontaneously or as a result of exposure to genotoxicants, can lead to constitutional chromosomal anomalies in the offspring. Alcohol is an established genotoxicant. The goal of this hypothesis-testing longitudinal cohort study was to evaluate the effect of significant/sustained maternal alcohol exposure on clinically diagnosed constitutional chromosomal anomalies among children diagnosed with fetal alcohol syndrome (FAS). De-identified eligibility and claim healthcare records, prospectively generated from the 1990-2012 Florida Medicaid system within the Independent Healthcare Research Database (IHRD), were analyzed. Children examined were continuously eligible with ≥ 8 outpatient office visits during the 96-month period following birth. Among these children, 377 were diagnosed with FAS and 137,135 were not. The incidence rate of chromosomal anomalies involving segregation (trisomy 13, 18, or 21, n = 625), microdeletions (microdeletion syndromes, n = 39), and point mutations (sickle-cell anemia/cystic fibrosis, n = 2570) were examined using frequency risk ratio (RR) and logistic regression (adjusted odds ratio (aOR) for sex, race, residence, socioeconomic/environmental exposure status, and birth date) models. The incidence rates of chromosomal anomalies involving segregation (RR=5.92, aOR=5.85) and microdeletions (RR=41.6, aOR=34.1) were significantly increased in the FAS cohort as compared to the non-diagnosed cohort, but there was no difference in the incidence rate of point mutations (RR=1.14, aOR=1.29). Maternal toxicant exposure should be considered in the etiology of constitutional chromosomal anomaly in offspring.

Ambiguous Genitalia: An Unexpected Diagnosis in a Newborn.

Alterations in gonad formation or function can lead to congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. These conditions are referred to as disorders of sex development (DSD) and have a heterogeneous etiology. The assessment of these children by a multidisciplinary team is crucial for an accurate diagnosis and should be initiated promptly due to the potentially life-threatening nature of congenital adrenal hyperplasia, a common cause of DSD. We present a neonate born at 39 weeks with a weak cry, slight hypotonia, poor suction reflex, peculiar facies, and ambiguous genitalia. From the study carried out, the abdominopelvic ultrasound revealed a nodular structure compatible with the left gonad. Aneuploidy screening confirmed the presence of the Y chromosome. Additionally, normal endocrinological studies and the karyotype showed a genotype compatible with cri-du-chat syndrome with partial trisomy of chromosome 3. Children with cri-du-chat syndrome characteristically exhibit a cat-like cry and distinctive facial features, along with developmental delay and intellectual disability. Duplication of 3p is a rare genetic disorder, usually associated with other chromosomal anomalies and congenital malformations, namely, of the genitals.

Cognitive-Behavioral Profile in Pediatric Patients with Syndrome 5p-; Genotype-Phenotype Correlationships.

(1) Background: 5p minus Syndrome (S5p-) is a neurodevelopmental disorder caused by a deletion in the short arm of chromosome 5. Among the phenotypic characteristics of S5p-, the most characteristic and representative element is a monochromatic cry with a high-pitched tone reminiscent of a cat's meow. Individuals may also show great phenotypic heterogeneity and great genetic variability. Regarding cognitive-behavioral aspects of the syndrome, the studies are scarce and do not establish a general profile of the main cognitive-behavioral particularities that this syndrome presents. The main objective of this work was to describe the development profile of a cohort of 45 children with 5p minus Syndrome, concerning the biomedical, genetic, cognitive, and behavioral aspects. Establishing putative genotype-phenotype (cognitive-behavioral profiles) relationships in our cohort, from an interdisciplinary approach. (2) Methods: A selection of instruments of measures was selected for neuropsychological assessment (3) Results: In general, children with S5p- have a higher cognitive level than a communicative and motor level. Language difficulties, especially expressive ones, influence the frequency and severity of the most frequent behavioral problems in S5p. The most significant problem behavior of children with S5p-, especially girls, is self-harm. Compulsive behavior, limited preferences, and interest in monotony are significantly more frequent in subjects with better cognitive levels. We also find a significant correlation between the size of the loss of genetic material on 5p and the cognitive level of the subjects. (4) Conclusions: We described for the first time, the cognitive-behavioral profile of a cohort of minors with S5p-. Remarkably, it was found that language, especially of an expressive nature, modulates the most frequent behavioral aspects in subjects with lower cognitive levels, so it is essential to develop verbal or alternative communication strategies adjusted to these individuals.

Cri-du-Chat Syndrome: Revealing a Familial Atypical Deletion in 5p.

Introduction: Cri-du-chat syndrome is generally diagnosed when patients present a high-pitched cry at birth, microcephaly, ocular hypertelorism, and prominent nasal bridge. The karyotype is useful to confirm deletions in the short arm of chromosome 5 (5p-) greater than 10 Mb. In cases of smaller deletions, it is necessary to resort to other molecular techniques such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA) or genomic array. Case Presentation: We report a family with an atypical deletion in 5p (mother and 2 children) and variable phenotypes compared with the literature. We applied a P064 MLPA kit to evaluate 5p- in the mother and the 2 children, and we used the Infinium CytoSNP-850K BeadChip genomic array to evaluate the siblings, an 11-year-old boy and a 13-year-old girl, to better define the 5p breakpoints. Both children presented a high-pitched cry at birth, but they did not present any of the typical physical features of 5p- syndrome. The MLPA technique with 5 probes for the 5p region revealed that the patients and their mother presented an atypical deletion with only 4 probes deleted (TERT_ex2, TERT_ex13, CLPTM1L, and IRX4). The genomic array performed in the siblings' samples revealed a 6.2-Mb terminal deletion in 5p15.33p15.32, which was likely inherited from their mother, who presented similar molecular features, seen in MLPA. Discussion: The sparing of the CTNND2 gene, which is associated with cerebral development, in both siblings may explain why these 2 patients had features such as better communication skills which most patients with larger 5p deletions usually do not present. In addition, both patients had smaller deletions than those found in patients with a typical 5p- phenotype. This report demonstrates the utility of genomic arrays as a diagnostic tool to better characterize atypical deletions in known syndromes such as 5p- syndrome, which will allow a better understanding of the genotype-phenotype correlations.

Esophageal Cancer with Early Onset in a Patient with Cri du Chat Syndrome.

BACKGROUND: In Cri du Chat (CdC), cancer as comorbidity is extremely rare. In databases from Denmark, Spain, Australia, New Zealand, and Japan, no cancer was reported; in Italy and Germany, four cancers were identified out of 321 CdCs. METHODS: In a 29-year-old CdC patient, clinical investigations following hematemesis led to the diagnosis of esophageal adenocarcinoma (EAC). A high pain threshold was also observed. Conventional and molecular cytogenetic defined the size of the deletion, and exome analysis on the trio completed the molecular work. RESULTS: Cytogenetic analysis showed a de novo chromosomal alteration: 46,XY,ishdel(5)(p14.3)(D5S28-) and arr[GRCh37] 5p15.33p14.3(1498180_19955760)x1. A quantitative sensory test demonstrated a high heat threshold. A 18f-fluorodeoxyglucose PET/TC scan of the brain failed to detect reduction of metabolism in the somatosensory area or insular cortex. Exome analysis in the trio (patient and parents) failed to identify variants to be interpreted as a likely risk factor for EAC. CONCLUSION: We conclude that the presence of well-known risk factors (maleness, obesity, gastroesophageal reflux, and Barrett's metaplasia) in a patient with very limited capability of expressing discomfort or referring clinical symptoms have been the main risk factors for developing EAC. At present, based on the available data, there is no evidence of any increased risk of developing cancer in CdC patients.

[Neonatal cri-du-chat syndrome revelead by facial dysmorphism and weak suction: a case report]. / Syndrome de cri du chat révélé par une dysmorphie cranio-faciale et faible succion chez un nouveau-né: à propos d'un cas.

Cri-du-chat syndrome is a rare genetic disorder, due to a deletion of the short arm of chromosome 5 (5p-). Its incidence is ranging from 1/15000 to 1/50000 live births. This was a one-day-old male newborn from a non-consanguineous marriage, the first pregnancy uncomplicated and carried to term with a birth weight of 2295g. Clinical examination revealed: craniofacial dysmorphism with hypertelorism and microcephaly, hypotonia, poor suction and clubfoot more marked on the right, the rest of the examination was unremarkable. During hospitalization, a high-pitched monochromatic cry mimicking a cat's meow was observed. The clinical diagnosis was confirmed by fluorescence in situ hybridization, showing a deletion of the short arm of chromosome 5 (5p15.2). The basic malformative work-up came back without any other abnormalities. The association of a high-pitched monochromatic cry with craniofacial dysmorphism in a newborn should indicate the need for cytogenetic study, in particular fluorescence in siti hybridization.

Long-Term Follow-Up on Bilateral Posterior Hypothalamic Deep Brain Stimulation for Treating Refractory Aggressive Behavior in a Patient with Cri du Chat Syndrome: Analysis of Clinical Data, Intraoperative Microdialysis, and Imaging Connectomics.

Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.

5p deletion with congenital diaphragmatic hernia: a case report.

BACKGROUND: 5p deletion syndrome is known as cri-du-chat syndrome, but there are no reports on congenital diaphragmatic hernia complications associated with it. CASE PRESENTATION: A 28-year-old primigravida Japanese woman was referred for 5 mm of nuchal translucency. Fetal growth restriction was found at 20 weeks, and a left-sided congenital diaphragmatic hernia was diagnosed at 24 weeks. The karyotype of the fetus was diagnosed as 46, XX, del(5)(p14) and referred to our hospital. At 36 + 6 weeks, a 1524 g female infant was delivered after premature membrane rupture, with Apgar scores of 4 and 6 at 1 and 5 minutes, respectively. The baby was intubated immediately with sedation and muscle relaxation, after birth for initial treatment for congenital diaphragmatic hernia. The peripheral blood karyotype was consistent with the prenatal result. The infant was discharged alive, without any respiratory support, after the defect of the diaphragm was repaired. CONCLUSION: The results of this study may be helpful for antenatal genetic counseling.

Tubo-ovarian abscess in a patient with cri du chat syndrome: A case report.

A tubo-ovarian abscess is an infection that occurs as a sequela of pelvic inflammatory disease. There is no reported association between a tubo-ovarian abscess and cri du chat syndrome in the medical literature. Herein, we report the case of a 44-year-old woman with cri du chat syndrome who was subsequently diagnosed with a tubo-ovarian abscess. After emergent laparotomy, simple total hysterectomy, and bilateral adnexectomy, the patient was discharged 13 days postoperatively without complications.

Prenatal Sonographic Features of Cri-du-Chat Syndrome: A Case Report and Analytical Literature Review.

Cri-du-Chat syndrome (CdCS) is a rare but serious genetic disorder. Most cases occur de novo, without specific risk factors as an indication of invasive prenatal diagnosis. Moreover, no specific ultrasound findings have been reported to facilitate early detection. This study presents a case of CdCS with fetal ultrasound findings of cerebellar hypoplasia and peri-membranous ventricular septal defect (VSD), which are consistent with previous reports, as well as coarctation of the aorta and hypercoiling cord, which have never been described in CdCS before. Additionally, we performed an analytical literature review to identify the sonographic pattern facilitating prenatal diagnosis. Based on the review of 47 reported cases, most CdCS fetuses (87.2%) had ultrasound characteristics: cerebellar hypoplasia (29.8%), followed by cardiac abnormalities (19.1%), hydrops fetalis/fluid collection (17.0%), ventriculomegaly (14.9%), choroid plexus cyst (12.8%) and nasal bone hypoplasia (12.8%). Increased nuchal translucency/nuchal fold thickness was also common. This is the first study providing a fetal sonographic pattern of CdCS that may facilitate early diagnosis.

Prenatal diagnosis of Cri-du-chat syndrome: analysis of 11 cases / 中华围产医学杂志

Objective:To investigate the ultrasonographic and genetic features of Cri-du-chat syndrome (CDCS).Methods:In this retrospective study, cases with CDCS diagnosed in Wuxi Maternal and Child Health Care Hospital from 2004 to 2021 and with complete data were reviewed to describe and analyze the maternal serum prenatal screening, non-invasive prenatal testing (NIPT), ultrasound, genetic examination data, and pregnancy outcomes.Results:All cases were diagnosed by karyotype analysis, seven of them were diagnosed prenatally through amniotic fluid, and four were diagnosed after birth through peripheral blood. Five of the seven cases diagnosed prenatally had an abnormal serological screening, including two cases with 5p- indicated by NIPT. Of the 11 cases, prenatal ultrasonography showed cerebellar transverse diameter less than －2 SD in eight cases, including four with cerebellar hypoplasia (CH), two with fetal growth restriction, and two with cranial diameters less than －2 SD. One case was shown with an increased nuchal translucency, accompanying bilateral choroid plexus cysts of the lateral ventricles, and suspected persistent left superior vena cava. No obvious ultrasound abnormality was observed in the remaining two cases. Among the seven cases diagnosed prenatally, excluding one case that refused parental verification, further single nucleotide polymorphism array (SNP array) showed that all six cases inherited the de novo mutations from the parents. The cytogenetic analysis found the breakpoints at 5p13, 5p14, and 5p15 in five, three, and three cases. All seven pregnancies were terminated in the second trimester. Four children diagnosed postnatally presented with CDCS phenotype during the follow-up at three years old. Conclusions:Fetal CDCS should be considered with CH detected by prenatal ultrasonography, though the correlation between CH and CDCS still needs further investigation. Gene mapping with an SNP array is helpful for phenotypic profiling and genetic counseling.

Long-term follow-up on bilateral posterior hypothalamic deep brain stimulation for treating refractory aggressive behavior in a patient with Cri du chat syndrome: analysis of clinical data, intraoperative microdialysis, and imaging connectomics

Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.

The general movements assessment and effects of an early intervention in an infant with Cri du chat syndrome: a case report.

BACKGROUND: Cri du chat syndrome (CdCS) is a rare orphan genetic disorder. Infants with CdCS have a neurodevelopmental dysfunction, but there are limited studies on their spontaneous movements or effect of the early interventions in children with CdCS. This study aimed to describe early spontaneous movements and investigate the effects of an early intervention in an infant with the CdCS. CASE: We analyzed the detailed general movements assessment (GMA) of an infant with CdCS at 14 weeks, and the Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) were used for the determining and the follow-up of developmental functioning at 14 weeks, 6 months and 12 months. The infant was included in an early intervention beginning from 14 weeks. Fidgety movements were absent. The motor repertoire appeared significantly reduced, and the movement character was monotonous at 14 weeks. Although the infant achieved some developmental milestones with the early intervention program, the improvements were not reflected in the Bayley-III composite score. CONCLUSIONS: As a consequence, abnormal GMA results, including fidgety movements and concurrent movement patterns, seen in CdCS can be associated with early signs of neurodevelopmental dysfunction. Early intervention programs in infants with genetic disorders could help enable the early achievement of motor milestones.

Prenatal diagnosis of Cri-du-Chat syndrome with concomitant distal trisomy 10q syndrome in one fetus with ultrasound anomalies.

OBJECTIVE: The aim of this work was to characterize the genetic abnormalities and prenatal diagnosis indications in one fetus with Cri-du-Chat syndrome with codependent 10q24.2-q26.3 duplication in prenatal screening. MATERIALS AND METHODS: A 31-year-old woman had a second trimester serum screening that indicated the fetus was at low risk. During this pregnancy, the woman underwent amniocentesis at 18+4 weeks' gestation because of adverse fertility history and nuchal fold thickening. Cytogenetic analysis and next-generation sequencing analysis were simultaneously performed to provide genetic analysis of fetal amniotic fluid. According to abnormal results, parental chromosome karyotype of peripheral blood was performed to analysis. RESULTS: CNV-seq detected a 14.00 Mb deletion at 5p15.33-p15.2 and a 34.06 Mb duplication at 10q24.2-q26.3 in the fetus. Cytogenetic analysis of the fetus revealed a karyotype of 46, XY, der(5) t(5;10) (p15.2;q26.3). The karyotype of pregnant women was 46,XX,t(5;10) (p15.2;q24.2). The pregnancy was subsequently terminated after sufficient informed consent. CONCLUSION: This is the first study that reports prenatal diagnosis of a Cri-du-Chat syndrome with concomitant 10 q24.2-q26.3 duplication. Adverse pregnancy history has to be as an important indicator for prenatal diagnosis, and the genetic factors of abnormal pregnancy should be identified before next pregnancy. Nuchal fold thickening is closely related to fetal abnormalities. Combined with ultrasonography, the use of CNV-seq will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.