Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood

Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.     

Family history interview of a broad phenotype in specific language impairment and matched controls

The aim was to study a broader phenotype of language‐related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention‐deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language‐related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language‐related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms.     

Copy Number Variation Screen Identifies a Rare De Novo Deletion at Chromosome 15q13.1-13.3 in a Child with Language Impairment

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1–13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.     

A major susceptibility locus for specific language impairment is located on 13q21

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.     

Association of specific language impairment (SLI) to the region of 7q31

FOXP2 (forkhead box P2) was the first gene characterized in which a mutation affects human speech and language abilities. A common developmental language disorder, specific language impairment (SLI), affects 6%-7% of children with normal nonverbal intelligence and has evidence of a genetic basis in familial and twin studies. FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region. In the present study, samples from children with SLI and their family members were used to study linkage and association of SLI to markers within and around FOXP2, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of FOXP2. No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the CFTR gene and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.     

Language,Reading, and Math Learning Profiles in an Epidemiological Sample of School Age Children

Dyscalculia, dyslexia, and specific language impairment (SLI) are relatively specific developmental learning disabilities in math, reading, and oral language, respectively, that occur in the context of average intellectual capacity and adequate environmental opportunities. Past research has been dominated by studies focused on single impairments despite the widespread recognition that overlapping and comorbid deficits are common. The present study took an epidemiological approach to study the learning profiles of a large school age sample in language, reading, and math. Both general learning profiles reflecting good or poor performance across measures and specific learning profiles involving either weak language, weak reading, weak math, or weak math and reading were observed. These latter four profiles characterized 70% of children with some evidence of a learning disability. Low scores in phonological short-term memory characterized clusters with a language-based weakness whereas low or variable phonological awareness was associated with the reading (but not language-based) weaknesses. The low math only group did not show these phonological deficits. These findings may suggest different etiologies for language-based deficits in language, reading, and math, reading-related impairments in reading and math, and isolated math disabilities.     

Association of D16S515 microsatellite with specific language impairment on Robinson Crusoe Island, an isolated Chilean population: a possible key to understanding language development

Specific language impairment (SLI) is a developmental language disorder that occurs for no known reason. The disorder affects 2-8% of children. Some scientific evidence suggests that genetic factors are implicated in the etiology of SLI. The disorder is genetically complex. Two novel loci, SLI1 on chromosome 16q24 (MIM 606711) and SLI2 on chromosome 19q13 (MIM 606712), have been found to be highly correlated with SLI. Four genes have been identified as susceptibility genes. SLI occurs at an unusually elevated incidence (35%) among the population of Robinson Crusoe Island (Chile), which also has a high consanguinity rate. This finding supports the influence of genetic mechanisms in the transmission of SLI based on a founder effect. To investigate further the genetic involvement in this population, we collected blood samples from 115 islanders from 13 families with a language-impaired proband and from 18 families with a normal-language proband. The analysis of micro satellite marker D16S515, located in locus SLI1, demonstrated that the 230-bp allele was correlated with SLI and that the 232-bp allele was correlated with normal language development. The domain containing the D16S515 marker, therefore, may play a role in language development.     

Pre-academic and early academic achievement in children with velocardiofacial syndrome (del22q11.2) of borderline or normal intelligence

School-aged children with del22q11.2 tend to show a typical learning and neuropsychological profile, which is characterised by a VIQ-PIQ discrepancy (in favour of the VIQ) and significantly better scores for reading (decoding) and spelling compared to mathematics. To the best of our knowledge, there exists no systematic research on the pre-academic and early academic skills that might underpin these learning difficulties. The purpose of the current study was to investigate more systematically these pre-academic and early academic skills in borderline to normal intelligent (FSIQ > 70) children with del22q11.2 in the last year of kindergarten and first grade of primary school in Flanders. In the kindergarten group, meta-linguistic awareness and counting skills were examined. In the group of first graders, children were tested on reading, spelling and mathematics. Thirteen children (mean age: 6 years 4 months (SD = 0.84); 9 boys, 4 girls) participated in this study. In the present study, there were no differences in intelligence and academic outcomes between boys and girls, and no differences in IQ and academic achievement between children with cardiac defects or severe velopharyngeal insufficiency (VPI) and children without these deficits. With regard to pre-academic achievement in general, a characteristic profile with clearly better results for meta-linguistic awareness in comparison to counting skills was found, but this difference is not statistically significant. Concerning early academic achievement, children with del22q11.2, as a group, perform (despite their somewhat lower general intelligence) on average compared with their age-related peers. However, at an individual level--especially within the domain of counting skills and mathematics--there is a wide variability, with some children showing remarkable learning difficulties already at an early age.     

Reduced Ventral Cingulum Integrity and Increased Behavioral Problems in Children with Isolated Optic Nerve Hypoplasia and Mild to Moderate or No Visual Impairment

Objectives

To assess the prevalence of behavioral problems in children with isolated optic nerve hypoplasia, mild to moderate or no visual impairment, and no developmental delay. To identify white matter abnormalities that may provide neural correlates for any behavioral abnormalities identified.

Patients and Methods

Eleven children with isolated optic nerve hypoplasia (mean age 5.9 years) underwent behavioral assessment and brain diffusion tensor imaging, Twenty four controls with isolated short stature (mean age 6.4 years) underwent MRI, 11 of whom also completed behavioral assessments. Fractional anisotropy images were processed using tract-based spatial statistics. Partial correlation between ventral cingulum, corpus callosum and optic radiation fractional anisotropy, and child behavioral checklist scores (controlled for age at scan and sex) was performed.

Results

Children with optic nerve hypoplasia had significantly higher scores on the child behavioral checklist (p<0.05) than controls (4 had scores in the clinically significant range). Ventral cingulum, corpus callosum and optic radiation fractional anisotropy were significantly reduced in children with optic nerve hypoplasia. Right ventral cingulum fractional anisotropy correlated with total and externalising child behavioral checklist scores (r = −0.52, p<0.02, r = −0.46, p<0.049 respectively). There were no significant correlations between left ventral cingulum, corpus callosum or optic radiation fractional anisotropy and behavioral scores.

Conclusions

Our findings suggest that children with optic nerve hypoplasia and mild to moderate or no visual impairment require behavioral assessment to determine the presence of clinically significant behavioral problems. Reduced structural integrity of the ventral cingulum correlated with behavioral scores, suggesting that these white matter abnormalities may be clinically significant. The presence of reduced fractional anisotropy in the optic radiations of children with mild to moderate or no visual impairment raises questions as to the pathogenesis of these changes which will need to be addressed by future studies.     

VEGF: a modifier of the del22q11 (DiGeorge) syndrome?

Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.     

Congenital heart defects in patients with DiGeorge/velocardiofacial syndrome and del22q11

Congenital heart defects (CHDs) are found in 75% of patients with DiGeorge/velocardiofacial (DG/VCF) syndromes with deletion 22q11.2 (del22q11). The purpose of this study was to analyse clinical features and, particularly, types and subtypes of CHDs associated with del22q11 in our series of patients and in those reported in other studies. All patients with CHD and del22q11 present major or minor clinical features of DG/VCF syndrome. Many children, particularly in the neonatal age, have only a "subtle" phenotype, so that accurate phenotypical evaluation is mandatory for selecting patients with CHD at risk for del22q11. Conotruncal cardiac defects are the most common CHDs in patients with DG/VCF syndrome, but other defects can also occur. Peculiar anatomical subtypes are found in patients with del22q11. They are frequently complex, consisting in malalignment with deficiency of the infundibular septum and anomalies of the aortic arch and pulmonary arteries.     

Problems with tense marking in children with specific language impairment: not how but when

Many children with specific language impairment (SLI) have persisting problems in the correct use of verb tense, but there has been disagreement as to the underlying reason. When we take into account studies using receptive as well as expressive language tasks, the data suggest that the difficulty for children with SLI is in knowing when to inflect verbs for tense, rather than how to do so. This is perhaps not surprising when we consider that tense does not have a transparent semantic interpretation, but depends on complex relationships between inflections and hierarchically organized clauses. An explanation in terms of syntactic limitations contrasts with a popular morpho-phonological account, the Words and Rules model. This model, which attributes problems to difficulties with applying a rule to generate regular inflected forms, has been widely applied to adult-acquired disorders. There are striking similarities in the pattern of errors in adults with anterior aphasia and children with SLI, suggesting that impairments in appreciation of when to mark tense may apply to acquired as well as developmental disorders.     

Development, problem behavior, and quality of life in a population based sample of eight-year-old children with Down syndrome

Objective

Children with Down syndrome (DS) have delayed psychomotor development. We investigated levels of development, problem behavior, and Health-Related Quality of Life (HRQoL) in a population sample of Dutch eight-year-old children with DS. Developmental outcomes were compared with normative data of eight-year-old children from the general population.

Method

Over a three-year-period all parents with an eight-year-old child with DS were approached by the national parent organization. Developmental skills were assessed by means of the McCarthy Scales of Children''s Ability. To measure emotional and behavioral problems we used the Child Behavior Checklist. HRQoL was assessed with the TNO-AZL Children''s Quality of Life questionnaire. Analyses of variance were applied to compare groups.

Results

A total of 337 children participated. Mean developmental age was substantially lower than mean calendar age (3.9 years, SD 0.87 and 8.1 years, SD 0.15 respectively). Mean developmental age was significantly lower among boys than girls (3.6 (SD 0.85) and 4.2 years (SD 0.82) respectively; p<0.001). Compared with the general population, children with DS had more emotional and behavioral problems (p<0.001). However on the anxious/depressed scale, they scored significantly more favorably (p<0.001). Significantly lower HRQoL scores for the scales gross motor skills, autonomy, social functioning and cognitive functioning were found (p-values<0.001). Hardly any differences were observed for the scales physical complaints, positive and negative emotions.

Conclusion

Eight-year-old children with DS have an average developmental delay of four years, more often have emotional and behavioral problems, and have a less favorable HRQoL compared with children from the general population.     

Tandem duplication of proximal 5q.

A 3.5-year-old boy with a de novo tandem duplication 5q11.1----5q15 is reported. Since the physical stigmata of seven liveborn cases with 5q proximal duplications are variable and inconspicuous, a recognizable syndrome could not be delineated. On the contrary, the associated developmental delay seems to be severe in duplications extending into 5q22 and mild in duplications 5q11----q13.     

The behavioural phenotype in velo-cardio-facial syndrome (VCFS): from infancy to adolescence

In this contribution the current status and recent findings of the behavioural phenotype in VCFS (22q11 deletion) are discussed with regard to motor development, cognition and neurodevelopment, and behaviour and temperament. Motor: hypotonia in infancy, gross-motor milestones are delayed, problems with coordination and balance from preschool age on, problems with tempo/speed during adolescence. Cognition and neurodevelopment: learning disabilities (82-100%), intellectual disability (45%), better verbal abilities than performal abilities, poor attention and concentration, visuo-perceptual-spatia problems, good (auditory) memory. An important subgroup of children (55%) has a non-verbal learning disability (NLD). Behaviour and social-emotional development AD(H)D, withdrawn and shy, person-dependent social problems in relationships with peers, anxious, risk for child psychiatric problems as well as for the development of psychiatric problems during adolescence and early adulthood. Information on the behavioural phenotype in VCFS (22q11 deletion) is of great importance to clinicians as an aid to syndrome diagnosis, but even more to parents because it offers immense direct practical value to the management of the behaviour of their child. Appropriate counseling and information on the long-term expectations, and better insight in the behaviour will lead to the development of realistic ways of coping with their child.     

Complex cytogenetic abnormalities in a patient with chronic myeloid leukemia: a case report

A case of multiple chromosome aberrations in a patient with CML (chronic myeloid leukemia) in the accelerated phase was described. Cytogenetic and molecular genetic studies revealed the presence of a t(9; 22)(q34; q11) translocation and some additional abnormalities such as t(1; 2)(p36; p21), del(6)(q21), +del(8)(q22), del(18)(q21), and +der(22), part of which is not typical for this kind of pathology. The correlation between the obtained data and the data presented in different publications is considered. A probable connection of the detected changes with previously received treatment and a possible effect of these changes on CML progression are discussed.