Parenting, family contexts, and personality characteristics in youngsters with VCFS

Parenting, family contexts, and personality characteristics in youngsters with VCFS: The personality profiles for 48 youths with Velo-Cardio-Facial syndrome (VCFS) were described using the California Child Q-Set (CCQ). Associations between personality characteristics and parenting (i.e., Control and Warmth vs. Anger) and family contexts (i.e., Experienced Family Stress, Marital Conflict and Parental Consistency) were investigated. Personality characteristics were found to be related to parenting (in particular, Parental Warmth vs. Anger) but not to family contexts. Parents who reported more Parental Warmth (and less Anger) in interactions had children with higher Agreeableness, Conscientiousness and Emotional Stability and with lower Irritability and Dependency. Parental Control was positively related to children's Dependency and negatively to children's Conscientiousness. Compared to fathers, mothers exerted more Control. Differences in parenting and family contexts were related to the mode of inheritance but not to IQ, age, gender, and cardiac defects. Families in which a familial deletion occurred reported higher levels of Marital Conflict and lower Warmth in the parent-child interactions.     

Excess of deletions of maternal origin in the DiGeorge/Velo-cardio-facial syndromes. A study of 22 new patients and review of the literature

We have determined the parental origin of the deleted chromosome 22 in 29 cases of DiGeorge syndrome (DGS) using a CA-repeat mapping within the commonly deleted region, and in one other case by using a chromosome 22 short arm heteromorphism. The CA-repeat was informative in 21 out of 29 families studied and the deleted chromosome was of maternal origin in 16 cases (72%). When these data are pooled with recent results from the literature, 24 de novo DGS, velo-cardio-facial syndrome (VCFS) and isolated conotruncal cardiac disease deletions are found to be of maternal origin and 8 of paternal origin, yielding a ² of 8 with a probability level lower than 0.01. These data, and review of the literature on familial DGS/VCFS and isolated conotruncal cardiopathies suggest that there is a strong tendency for the 22q11.2 deletions to be of maternal origin.     

Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors

Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥ 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥ 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.     

22q11 deletions in isolated and syndromic patients with tetralogy of Fallot

Tetralogy of Fallot (TF) is a congenital conotruncal heart defect commonly found in DiGeorge (DGS) and velo-cardio-facial (VCFS) syndromes. The deletion of chromosome 22q11 (de122q11) is a well established cause of DGS and VCFS, and it has been demonstrated also in sporadic or familial cases of TF. In order to investigate the prevalence of de122q11 in patients with TF, we analyzed the DNA of 137 consecutive patients with syndromic and isolated TF, using the HD7k probe, which detects hemizygosity for the D22S134 locus. De122q11 has been detected in 11/26 (42%) syndromic patients. Evidence for hemizygosity was obtained in all patients with DGS and in 8/15 patients with VCFS. None of the 107 patients with isolated TF had de122q11. Our experience suggests that children with TF and de122q11 always present major or minor extracardiac anomalies. These features, including subtle facial dysmorphisms, should be checked routinely in patients with TF and other conotruncal heart defects.     

Mathematical disabilities in young primary school children with velo-cardio-facial syndrome

The aim of the present study was to examine the previously reported mathematical disabilities (MD) of children with Velo-Cardio-Facial Syndrome (VCFS) in children of a younger age range. Fourteen children with VCFS (aged 6-10 years) participated in this study. These children were individually matched on sex, IQ, age and parental educational level to a control group of peers, selected from the same classes. A broad range of mathematical abilities were assessed, comprising number reading and writing, number comparison, counting, single-digit arithmetic, multidigit arithmetic and word problem solving. Consistent with previous reports, children with VCFS were significantly slower in counting numerosities and they tended to perform more poorly on number comparison. These results indicate that difficulties in low-level number processing in children with VCFS occur already at a very young age. Furthermore, children with VCFS demonstrated preserved retrieval of arithmetic facts, but, in contrast to older children with VCFS, no procedural difficulties in mathematics were observed. Finally, word problem solving appeared to be an important area of weakness, starting already at this young age.     

MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P<.001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female:male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.     

Translocation Down syndrome in Ohio 1970-1981: epidemiologic and cytogenetic factors and mutation rate estimates.

Sixteen hundred eighty-eight Down syndrome live births, including 65 (5.2%) translocations, were ascertained in Ohio between 1970 and 1981. Translocations of known origin were 24.4% maternal, 2.2% paternal, and 73.3% de novo. Translocation subtypes were 14/21 (45.7%), 15/21 (2.9%), 21/21 (40.0%), 21/22 (2.9%), and other (8.5%). Among 14/21 translocations, 33.3% were maternal in origin and 66.7% were de novo, while 100% of 21/21 translocations were de novo. No differences were found when the maternal- and paternal-age distributions of all translocations or various translocation subsets were compared with the live-birth control distributions. However, mean maternal and paternal ages of de novo translocations were significantly lower than that of the live-birth controls. Ohio data showed the average maternal age of de novo D/21 cases to be significantly lower than the control. Ages of both parents of de novo G/21 cases and paternal age of D/21 cases were not different from the control. De novo translocation mutation rate estimates were 0.8 X 10(-5) for 14/21, 1.2 X 10(-5) for 21/21, and 2.2 X 10(-5) overall. Ohio estimates (3.2 X 10(-5) for 1970-1972 and 1.4 X 10(-5) for 1973-1975) did not reflect the increase in mutation rate previously found in New York during 1973-1977.     

Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome

Germline mutations in PTPN11--the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2--represent a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders, a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.     

Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders.

Velo-cardio-facial syndrome (VCFS) is characterized by conotruncal cardiac defects, cleft palate, learning disabilities, and characteristic facial appearance and is associated with hemizygous deletions within 22q11. A newly recognized clinical feature is the presence of psychiatric illness in children and adults with VCFS. To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, we evaluated 26 VCFS patients by clinical and molecular biological methods. The VCFS children and adolescents were found to share a set of psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients, >18 years of age, were affected with bipolar spectrum disorders. Four of six adult patients had psychotic symptoms manifested as paranoid and grandiose delusions. Loss-of-heterozygosity analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal deletion and two did not have a detectable deletion. Somatic cell hybrids were developed from the two patients who did not have a detectable deletion within 22q11 and were analyzed with a large number of sequence tagged sites. A deletion was not detected among the two patients at a resolution of 21 kb. There was no correlation between the phenotype and the presence of the deletion within 22q11. The remarkably high prevalence of bipolar spectrum disorders, in association with the congenital anomalies of VCFS and its occurrence among nondeleted VCFS patients, suggest a common genetic etiology.     

Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the causes of sudden cardiac death in young people and results from RYR2 mutations in ~60% of CPVT patients. The inheritance of the RYR2 mutations follows an autosomal dominant trait, however, de novo mutations are often identified during familial analysis. In 36 symptomatic CPVT probands with RYR2 mutations, we genotyped their parents and confirmed the origin of the respective mutation. In 26 sets of proband and both parents (trio), we identified 17 de novo mutations (65.4%), seven from their mothers and only two mutations were inherited from their fathers. Among nine sets of proband and mother, five mutations were inherited from mothers. Four other mutations were of unknown origin. The inheritance of RYR2 mutations was significantly more frequent from mothers (n = 12, 34.3%) than fathers (n = 2, 5.7%) (P = 0.013). The mean ages of onset were not significantly different in probands between de novo mutations and those from mothers. Thus, half of the RYR2 mutations in our cohort were de novo, and most of the remaining mutations were inherited from mothers. These data would be useful for family analysis and risk stratification of the disease.     

Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion

Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ～3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.     

Parental origin of germ-line and somatic mutations in the retinoblastoma gene

Segregation analysis of polymorphic sites within the retinoblastoma (RB) gene and on chromosome 13, as well as the parental origin of the lost allele in the tumor, were analyzed in 24 families with RB patients. Four mutant alleles transmitted through the germ-line and seven de novo germ-line mutant alleles were identified in 11 patients with hereditary RB. Segregation analysis within the RB gene and on chromosome 13 was useful for DNA diagnosis of susceptibility to RB in relatives of hereditary patients, even if mutations were not identified. All seven de novo germ-line mutant alleles were paternally derived. The bias toward the paternal allele for de novo germ-line mutations of the RB gene was statistically significant. Seven paternal alleles and six maternal alleles were lost in 13 non-hereditary RB tumors with no bias in the parental origin of the somatic allele loss. These results suggest that the physical environment or a deficiency in DNA repair during spermatogenesis may be associated with significant risk factors for de novo germ-line mutations.     

De novo paracentric inversion 14q13q24.1 in a patient with severe involuntary movements, epilepsy, oligodontia and dysmorphic features

We describe a 22-year-old woman with a de novo paracentric inversion of the long arm of chromosome 14 with breakpoints at q13 and q24 and associated with epilepsy, dysarthria and severe incapacitating involuntary movements present since birth. These movements were incessant when awake but absent when asleep. She had unusual facies with downward slant of palpebral fissures, epicanthi, broad philtral groove, flat malar region, large, cup shaped and low-set ears, and short neck. Her decidual and permanent dentition lacked all premolars and molars. Psychological assessment at ages 6 and 15 years showed mild mental retardation. In spite of the aggravation of the neurological symptoms no decline of mental capacity was observed. A brain MRI was normal at 19 years of age. Early on EEG showed changes compatible with partial epilepsy, and at later stages there was, contrary to expectation, only a mild background slowing. Urinary metabolic screening tests and a search for vacuolated lymphocytes were negative. Previously, four cases with a similar inversion have been described. Of these, three were familial with normal phenotype, and the fourth was de novo with severe mental retardation, microcephaly and involuntary movements. Our case is the second de novo inversion of the long arm of chromosome 14 with breakpoints at q13 and q24. The observations in the two patients suggest that this chromosomal rearrangement is associated with a congenital complex movement disorder.     

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.     

Familial non-syndromic conotruncal defects are not associated with a 22q11 microdeletion

Molecular studies have shown microdeletions in region q11 of chromosome 22 in nearly all patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes (DGS, VCFS and CTAFS, respectively) and in a high percentage of non-syndromic familial cases of conotruncal defects (CTD). CTD account for roughly a fourth to a third of all non-syndromic congenital heart defects (CHD), thus, 22q11 could harbor a major genetic factor of CHD. We searched for a 22q11 microdeletion in familial cases of non-syndromic CTD. Thirty-six cases of various isolated CTD, that is without history of hypocalcemia, immune deficiency, absent thymus, and dysmorphic appearance, were selected. With 48178, a cosmid probe localized in the smallest deleted region of the DiGeorge critical region (DGCR), we found no deletions by fluorescence in situ hybridization in these 36 affected individuals of 16 families with recurrent CTD. Moreover, D22S264, a microsatellilte localized at the distal part of the largest deleted region, was used to genotype the patients. Thirty-two patients out of 37 were heterozygous and hence not deleted at this locus, whereas 5 were uninformative. In conclusion, there are no large deletions in familial cases of various CTD, whether these defects are identical or not within a family. This result does not rule out other minor anomalies in this chromosomal region.     

Mutation analysis of UBE3A in Angelman syndrome patients.

Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.     

The significance of accessory bisatellited marker chromosomes in amniotic fluid cell cultures

Thirteen new cases of accessory bisatellited marker chromosomes were found among 20,370 amniocentesis. Six of these were familial, six originated de novo and in one case the origin of marker chromosome remained unknown. Eleven cases were carried to term and follow up studies revealed no abnormality. In two cases the pregnancies were terminated and the pathological examination revealed apparently normal fetuses. A cytogenetic categorization of bisatellited marker chromosomes is described. The available data show clearly that there is no increased risk for offspring with abnormal phenotype born to a healthy carrier of an accessory bisatellited marker chromosome with either a single or two closely adjacent C-bands (category AI or AII). The unbiased sample of cases with de novo accessory bisatellited marker chromosomes of category AI or AII is still too small to allow a satisfactory estimation. However, the actual risk for a fetus to be affected may be low too.     

11q- syndrome: three cases and a review of the literature.

We report on three children with de novo terminal deletions of the long arm of chromosome 11 (11q-) and breakpoints in 11q23-q24. Eighty-nine other patients with partial monosomy 11q have been reported and were reviewed by us. Salient features of 11q- syndrome are psychomotor retardation, trigonocephaly, telecanthus/hypertelorism, broad depressed nasal bridge, micrognathia, low set abnormal ears, cardiac anomalies and hand/foot anomalies. Renal agenesis and anal atresia are reported first here. Supratentorial white matter abnormality on CT and MRI present in our second patient was reported in three patients. Increased mortality is caused by cardiac anomalies. A third of all patients with partial monosomy 11q had thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q23-q24. Seventy-six percent of patients have de novo deletions with breakpoints in 11q21-q25. There is no obvious correlation between the length of the deleted segment and the severity of the symptoms. In unbalanced chromosomal patterns with deletions of 11q involving bands 11q23-q24 the typical phenotype of 11q- syndrome remains recognizable. Deletions distal to 11q24.1 do not produce the typical 11q- syndrome.     

A new RFLP withStuI and probe cX55.7 (DXS105) and its usefulness in carrier analysis of fragile X syndrome

Summary The case of a healthy 29-year-old woman is reported who had a history of three early spontaneous abortions. Chromosomal analysis of the mother of the patient showed a balanced karotype of 46,XX,t(6;11)(q24; q21), whereas the chromosomes of her father were normal. The karotype of this patient is thus a combination of a familial translocation 6;11 and a de novo translocation 4;11, which is very rare.     

“Are CRT upgrade procedures more complex and associated with more complications than de novo CRT implantations?” A single centre experience

Objective

The objective of the study was to examine whether cardiac resynchronisation therapy upgrade procedures are more complex and associated with more complications than de novo implantations.

Method

We retrospectively compared 134 upgrade procedures performed between 2006–2012 with a random, equally sized, sample of de novo CRT device implantations in the same period. Procedural data and the occurrence of periprocedural (≤ 30 days) and long-term device-related (≤ 1 year) complications were analysed. Complications with consequences were defined as those in need of adjustment of standard care.

Results

Median time to upgrade was 57 (31–115) months. There were no significant differences in procedure duration, radiation time or total hospitalisation between upgrades and de novo implantations. Perioperative complications occurred in 6.7 % of upgrade patients and in 9.0 % of de novo patients. The most frequently seen complications were phrenic nerve stimulation, coronary sinus dissection and pocket haematoma. Procedure success was comparable (upgrade: 98.5 % versus de novo: 96.3 %). A total of 236 patients completed 1 year of follow-up. Ten (4.2 %) patients had a long-term device-related complication with consequences including phrenic nerve stimulation, lead dislodgement/dysfunction, and infection (upgrade: 3.5 % versus de novo: 4.9 %).

Conclusion

Upgrade procedures are not more complex nor associated with more complications than de novo CRT implantations.