Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage.
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ABSTRACT:
SUBMITTER: Dale B
PROVIDER: S-EPMC5677976 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS.
| S-EPMC5961083 | biostudies-literature
Project description:BACKGROUND: Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date. METHODS: We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents. RESULTS: Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping. CONCLUSION: The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.
| S-EPMC2700091 | biostudies-literature
Project description:Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.
| S-EPMC6705695 | biostudies-literature
Project description:One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD.
| S-EPMC3961203 | biostudies-literature
Project description: Not available
| S-EPMC8930283 | biostudies-literature
Project description:Misalignments of low-copy repeats (LCRs) located in chromosome 22, particularly band 22q11.2, predispose to rearrangements. A variety of phenotypic features are associated with 22q11.2 microduplication syndrome which makes it challenging for the genetic counselors to recommend appropriate genetic assessment and counseling for the patients. In this study, multiplex ligation probe dependent amplification (MLPA) analysis was performed on 378 patients with cleft lip and/or palate to characterize rearrangements in patients suspected of 22q11.2 microduplication and microdeletion syndromes. Of 378 cases, 15 were diagnosed with a microdeletion with various sizes and 3 with duplications. For the first time in this study an atypical 0.6 Mb duplication is reported. Illustration of the phenotypes associated with the microduplications increases the knowledge of phenotypes reported in the literature.
| S-EPMC4660028 | biostudies-literature
Project description:The 22q11.2 microduplication syndrome shows variable phenotypes with reduced penetrance compared to the 22q11.2 deletion syndrome. We report a woman with overgrowth and macrocephaly, mild mental retardation, heart defect, kidney anomalies, and dysmorphic features. Array-CGH analysis revealed a 246-kb duplication at the 22q11.2 region. No additional clinically significant CNVs were found. The case resembles a previously published case also showing overgrowth and macrocephaly with an almost identical 22q11.2 duplication of 252 kb.
| S-EPMC8117256 | biostudies-literature
Project description:BACKGROUND:Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS:We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS:We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION:Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.
| S-EPMC6393688 | biostudies-literature
Project description:Copy number variation (CNV) of human chromosome 22q11.2 is associated with an elevated rate of autism spectrum disorder (ASD) and represents one of syndromic ASDs with rare genetic variants. However, the precise genetic basis of this association remains unclear due to its relatively large hemizygous and duplication region, including more than 30 genes. Previous studies using genetic mouse models suggested that although not all 22q11.2 genes contribute to ASD symptomatology, more than one 22q11.2 genes have distinct phenotypic targets for ASD symptoms. Our data show that deficiency of the two 22q11.2 genesTbx1 and Sept5 causes distinct phenotypic sets of ASD symptoms.
| S-EPMC4118685 | biostudies-literature
Project description:Deletions and duplications at the 22q11.2 locus are associated with significant neurodevelopmental and psychiatric morbidity. Previous diffusion-weighted magnetic resonance imaging (MRI) studies in 22q11.2 deletion carriers (22q-del) found nonspecific white matter (WM) abnormalities, characterized by higher fractional anisotropy. Here, utilizing novel imaging and processing methods that allow separation of signal contribution from different tissue properties, we investigate whether higher anisotropy is driven by (1) extracellular changes, (2) selective degeneration of secondary fibers, or (3) volumetric differences. We further, for the first time, investigate WM microstructure in 22q11.2 duplication carriers (22q-dup). Multi-shell diffusion-weighted images were acquired from 26 22q-del, 19 22q-dup, and 18 healthy individuals (HC). Images were fitted with the free-water model to estimate anisotropy following extracellular free-water elimination and with the novel BedpostX model to estimate fractional volumes of primary and secondary fiber populations. Outcome measures were compared between groups, with and without correction for WM and cerebrospinal fluid (CSF) volumes. In 22q-del, anisotropy following free-water elimination remained significantly higher compared with controls. BedpostX did not identify selective secondary fiber degeneration. Higher anisotropy diminished when correcting for the higher CSF and lower WM volumes. In contrast, 22q-dup had lower anisotropy and greater extracellular space than HC, not influenced by macrostructural volumes. Our findings demonstrate opposing effects of reciprocal 22q11.2 copy-number variation on WM, which may arise from distinct pathologies. In 22q-del, microstructural abnormalities may be secondary to enlarged CSF space and more densely packed WM. In 22q-dup, we see evidence for demyelination similar to what is commonly observed in neuropsychiatric disorders.
| S-EPMC8581007 | biostudies-literature