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Introduction: There are more than 6000 genetic syndromes, therefore the recognition of facial patterns may present a challenge for clinicians. The 22q11.2 deletion syndrome (22q11.2 DS) and Williams syndrome (WS) are two different genetic syndromes but share some common phenotypic traits and subtle facial dysmorphisms. Therefore, any tool that would help clinicians recognize genetic syndromes would likely result in a more accurate diagnosis. Methods: The syndrome identification accuracy was compared between 2 different facial analysis algorithms (DeepGestalt and GestaltMatcher) of the Face2Gene (F2G) tool and a group of 9 clinicians with different levels of expertise before and after using F2G for a cohort of 64 Thai participants' frontal facial photos divided into 3 groups of 22q11.2 DS, WS and unaffected controls. Results: The higher accuracy from the DeepGestalt algorithm than from clinicians was demonstrated, especially when comparing between the two syndromes. The accuracy was highest when clinicians use the tool combined with their own decision-making process. The tool's second algorithm, GestaltMatcher revealed clear separation among these three groups of photos. Discussion: The result of F2G outperforming clinicians was not surprising. However, the highest increase in accuracy was with nondysmorphology clinicians using F2G. Conclusion: Face2Gene would be a useful tool to help clinicians in facial recognition of genetic syndromes, before ordering specific tests to confirm the definite diagnosis. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype. [ABSTRACT FROM AUTHOR]

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation. [ABSTRACT FROM AUTHOR]

The clinical expression of 22q11.2 deletion syndrome (22q11.2 DS) is extremely variable, as patients can present with recurrent or severe infections, immune dysregulation, atopic diseases, or extra-immunological manifestations. The immunological background underlying the different disease manifestations is not completely elucidated. The aim of this study was to identify the immunophenotypic peculiarities of 22q11.2 DS patients presenting with different disease expressions. This study included 34 patients with 22q11.2 DS, divided into three groups according to the clinical phenotype: isolated extra-immunological manifestations (G1), infectious phenotype with increased/severe infections (G2), and immune dysregulation (G3). The patients underwent extended immunophenotyping of the T and B lymphocytes and analysis of the circulating dendritic cells (DCs). In patients with an infectious phenotype, a significant reduction in CD3+ and CD4+ cells and an expansion of CD8 naïve cells was evidenced. On the other hand, the immunophenotype of the patients with immune dysregulation showed a skewing toward memory T cell populations, and reduced levels of recent thymic emigrants (RTEs), while the highest levels of RTEs were detected in the patients with isolated extra-immunological manifestations. This study integrates the current literature, contributing to elucidating the variability in the immune status of patients with 22q11.2DS with different phenotypic expressions, particularly in those with infectious phenotype and immune dysregulation. [ABSTRACT FROM AUTHOR]

The article describes a case of respiratory distress and hypocalcemia in a 2-week-old boy, leading to the diagnosis of DiGeorge syndrome, emphasizing the importance of considering a wide range of differentials for electrolyte imbalances in infants. Topics include differential diagnosis of hypocalcemia in newborns, phenotypic features and diagnostic workup of DiGeorge syndrome, and the necessity of a multidisciplinary approach in managing associated abnormalities.

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome. [ABSTRACT FROM AUTHOR]

Social impairments are common features of 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). The Ecological Momentary Assessment (EMA) allowed access to daily-life information in order to explore the phenomenology of social interactions. 32 individuals with 22q11DS, 26 individuals with ASD and 44 typically developing peers (TD) aged 12–30 were assessed during 6 days 8 times a day using a mobile app. Participants with 22q11DS and ASD did not spend more time alone but showed distinct implication in the social sphere than TD. Distinct profiles emerged between the two conditions regarding the subjective experience of aloneness and the subjective experience of social interactions. This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD that points towards different therapeutic targets. [ABSTRACT FROM AUTHOR]

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (~13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome (22q11DS) is characterised by a complex behavioural phenotype including anxiety, attention-deficit/hyperactivity disorder and psychosis. In the current study, we aimed at improving our understanding of the heterogeneity of behavioural characteristics in a group of 129 young people (aged 4–22) with a confirmed 22q11.2 microdeletion and 116 age and gender matched typically developing controls. Half the participants with 22q11DS had behaviour characterised by emotion dysregulation. A cluster analyses, of the participants with 22q11DS, revealed four groups characterised by intact emotion regulation; predominantly internalizing problems; both internalizing and externalizing problems; and predominantly externalizing difficulties. Importantly, it was found that young people with 22q11DS whose emotion dysregulation was characterised by externalizing problems had the poorest levels of functioning. As our understanding of 22q11DS improves, it is becoming increasingly clear that we need a better understanding of how individual differences and psychosocial factors contribute to, and interact with one another, to result in the observable individual differences in the 22q11DS behavioural phenotype. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion is one of the most common genetic microdeletions, affecting approximately 1 in 4000 live births in humans. A 1.5 to 2.5 Mb hemizygous deletion of chromosome 22q11.2 causes DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). DGS/VCFS are associated with prevalent cardiac malformations, thymic and parathyroid hypoplasia, and craniofacial defects. Patients with DGS/VCFS manifest craniofacial anomalies involving the cranium, cranial base, jaws, pharyngeal muscles, ear-nose-throat, palate, teeth, and cervical spine. Most craniofacial phenotypes of DGS/VCFS are caused by proximal 1.5 Mb microdeletions, resulting in a hemizygosity of coding genes, microRNAs, and long noncoding RNAs. TBX1, located on chromosome 22q11.21, encodes a T-box transcription factor and is a candidate gene for DGS/VCFS. TBX1 regulates the fate of progenitor cells in the cranial and pharyngeal apparatus during embryogenesis. Tbx1-null mice exhibit the most clinical features of DGS/VCFS, including craniofacial phenotypes. Despite the frequency of DGS/VCFS, there has been a limited review of the craniofacial phenotypes of DGC/VCFS. This review focuses on these phenotypes and summarizes the current understanding of the genetic factors that impact DGS/VCFS-related phenotypes. We also review DGS/VCFS mouse models that have been designed to better understand the pathogenic processes of DGS/VCFS. [ABSTRACT FROM AUTHOR]

DiGeorge Syndrome Critical Region Gene 8 (DGCR8) is a key component of the microprocessor complex governing the maturation of most microRNAs, some of which participate in schizophrenia and neural development. Previous studies have found that the 22q11.2 locus, containing DGCR8, confers a risk of schizophrenia. However, the role of DGCR8 in schizophrenia and the early stage of neural development has remained unknown. In the present study, we try to identify the role of DGCR8 in schizophrenia from human samples and animal models. We found that the G allele and GG genotype of rs3757 in DGCR8 conferred a higher risk of schizophrenia, which likely resulted from higher expression of DGCR8 according to our test of dual-luciferase reporter system. Employed overexpression model in utero and adult mice, we also revealed that the aberrant increase of Dgcr8 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice. Together, these results demonstrate that DGCR8 may play a role in the etiology of schizophrenia through regulating neural development. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS. [ABSTRACT FROM AUTHOR]

22q11.2-deletion syndrome is a genetic disorder caused by a small deletion of chromosome 22. This deletion often results in developmental delays, learning disabilities, medical conditions, and comorbid psychiatric conditions. Patients with 22q11.2DS may present with a variety of behavioral phenotypes including obsessiveness and rigidity, poor social skills, and anxiety. In some cases, the phenotype can consist of destructive and inappropriate behavior including harming self and others. Behavioral difficulties are reported as one of the most challenging aspects of 22q11.2-deletion syndrome for families of patients, however, few studies have examined behavioral interventions as a possible therapeutic treatment for this population. Using principles derived from operant-behavioral psychology, we conducted functional assessments to determine the environmental correlates of destructive and inappropriate behaviors in two adult men with 22q11.2-deletion syndrome. Subsequently, behavioral interventions based on differential reinforcement were incorporated into each participant's natural environment to eliminate these behaviors. Significant reductions in destructive and inappropriate behavior were observed with both participants and therapeutic gains were maintained at follow-up. We discuss the role of behavioral interventions in combination with appropriate psychotropic medication when addressing challenging behaviors in this population. [ABSTRACT FROM AUTHOR]

Background: The diagnostic journey for many rare disease patients remains challenging despite use of latest genetic technological advancements. We hypothesize that some patients remain undiagnosed due to more complex diagnostic scenarios that are currently not considered in genome analysis pipelines. To better understand this, we characterized the rare disorder (RD) spectrum using various bioinformatics resources (e.g., Orphanet/Orphadata, Human Phenotype Ontology, Reactome pathways) combined with custom-made R scripts.Results: Our in silico characterization led to identification of 145 borderline-common, 412 rare and 2967 ultra-rare disorders. Based on these findings and point prevalence, we would expect that approximately 6.53%, 0.34%, and 0.30% of individuals in a randomly selected population have a borderline-common, rare, and ultra-rare disorder, respectively (equaling to 1 RD patient in 14 people). Importantly, our analyses revealed that (1) a higher proportion of borderline-common disorders were caused by multiple gene defects and/or other factors compared with the rare and ultra-rare disorders, (2) the phenotypic expressivity was more variable for the borderline-common disorders than for the rarer disorders, and (3) unique clinical characteristics were observed across the disorder categories forming the spectrum.Conclusions: Recognizing that RD patients who remain unsolved even after genome sequencing might belong to the more common end of the RD spectrum support the usage of computational pipelines that account for more complex genetic and phenotypic scenarios. [ABSTRACT FROM AUTHOR]

Interestingly, most patients diagnosed with PG also suffer from underlying diseases such as inflammatory bowel disease, inflammatory arthritis, or hematologic disorders. We report here a complex case of PG in a patient with immune deficiency leading to the diagnosis of 22q11.2 deletion syndrome. Some studies have reported PG or PG-like neutrophilic dermatosis in other PID patients (leucocyte adhesion deficiency, RAG) [[6]], but to our best knowledge never in 22q11.2 deletion syndrome. [Extracted from the article]

The discovery that overexpressing one or a few critical transcription factors can switch cell state suggests that gene regulatory networks are relatively simple. In contrast, genome-wide association studies (GWAS) point to complex phenotypes being determined by hundreds of loci that rarely encode transcription factors and which individually have small effects. Here, we use computer simulations and a simple fitting-free polymer model of chromosomes to show that spatial correlations arising from 3D genome organisation naturally lead to stochastic and bursty transcription as well as complex small-world regulatory networks (where the transcriptional activity of each genomic region subtly affects almost all others). These effects require factors to be present at sub-saturating levels; increasing levels dramatically simplifies networks as more transcription units are pressed into use. Consequently, results from GWAS can be reconciled with those involving overexpression. We apply this pan-genomic model to predict patterns of transcriptional activity in whole human chromosomes, and, as an example, the effects of the deletion causing the diGeorge syndrome. Gene-regulatory networks are thought to be complex, and yet perturbation of just a few transcription factors (TFs) can have major consequences. Here the authors apply DNA polymer modelling and simulations to predict how 3D genome structure and TF-DNA interactions can give rise to transcriptional regulation operating over broad genomic regions, where small perturbations can have long-reaching effects. [ABSTRACT FROM AUTHOR]

Objectives: Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency. Experimental Approach: Disease model : Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain. Methods: In situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved. Results: Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression. Conclusion: To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region. [ABSTRACT FROM AUTHOR]

Background: Individuals with 22q11.2 deletion syndrome (22q11.2DS) exhibit various phenotypes. Objective: To compare the clinical and otorhinolaryngological features of Japanese patients with 22q11.2DS with those of patients reported in Western literature. Materials and methods: We retrospectively assessed the medical records of 17 Japanese patients with 22q11.2DS and compared our findings with previously reported findings in Western literature. Results: Hearing loss was the most frequent complaint (n = 8, 47%), followed by articulation disorders and/or nasopharyngeal closure failure (n = 4, 24%) and language development delay (n = 2, 12%). Ten patients (59%) had hearing loss regardless of the chief complaint (total 15 ears – mild, 9; moderate, 6). Four patients had bilateral hearing loss. One patient (6%) underwent tympanostomy tube placement for refractory exudative otitis media, another (6%) underwent myringoplasty, and three patients (18%) underwent tympanoplasties for chronic otitis media or middle ear malformation. Previous studies in Western countries reported similar results in terms of frequency of hearing loss, severity of hearing loss, and the percentage of middle ear malformations. Conclusions: The otorhinolaryngological characteristics of Japanese patients with 22q11.2DS were similar to those in Western countries. Hearing loss was primarily caused by disorders like otitis media and middle ear malformation. Significance: Our findings may aid treatment planning for Asian patients with 22q11.2DS. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to evaluate the incidence of genetic abnormalities in operated congenital heart disease patients and the influence of underlying genetic issues on morbidity and mortality of these patients. Methods: The medical records of the operated patients at our cardiac center were evaluated retrospectively. Patients were evaluated as syndromic or nonsyndromic(without any syndrome) according to their genetic test results or phenotypes. The surgical results were evaluted by scoring systems. The primary end points were accepted as mortality(in the first postoperative30 days) and morbidity (>7days of ICU monitorization). Results: Total 2330 patients operated between 01.01.2013 and 01.01.2018 were included in the study. The median age and body weight were 6.5 months(range: 1 day-18 years) and 7.2 kg(1-80 kg) respectively.55% were males(n=1285), 20% were <1 month old,58% were <1 year of age. A defined genetic syndrome was present in 15% (n=344)(Down syndrome(n=207), DiGeorge syndrome (n=38) and another genetic syndrome (n=99). Overall mortality was 26.2%(n=601). Mortality in sugroups were 6.6% in nonsyndromics,7.2% in Down syndrome, 13.1% in Di George Syndrome respectively. Mortality was found significantly high in only Di George syndrome (p=0.04). Overall morbidity was 26.2% (n=601). Subgroup morbidities was 25.6% in nonsyndromic patients,26.1% in Down syndrome, 42.1% in DiGeorge Syndrome,33.3% in other groups. Morbidity was significantly high in groups with Di George Syndrome and other syndromes groups(p=0.02). Conclusion: The presence of a syndrome causes an increase in morbidity due to prolonged ICU duration but does not effect the mortality rates. The advanced ICU care has a great effect on that. The proper management of patients with congenital heart disease and associated genetic syndrome will help to improve the ultimate results [ABSTRACT FROM AUTHOR]

The objective of this work was to identify 22q11.2 chromosomal deletion in patients with cleft lip and/or cleft palate and suggestive syndromic phenotype in Colombian patients. We studied 49 patients with cleft lip and/or cleft palate, exhibiting additional clinical findings linked to 22q11.2 deletion syndrome. All patients underwent high-resolution G-banded karyotyping, multiplex ligation-dependent probe amplification, and clinical evaluation by a geneticist. Seven patients presented 22q11.2 deletion and 2 patients had other chromosomal abnormalities. In conclusion, this study contributes with new data for genetic etiology in syndromic conditions of oral fissures. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome (22q11.2DS) is one of the most frequent microdeletion syndromes and presents with a highly variable phenotype. In most affected individuals, specific but subtle facial features can be seen. In this observational study, we aim to investigate the craniofacial and dental features of 20 children with a confirmed diagnosis of 22q11.2DS by analyzing 3-dimensional (3D) facial surface scans, 2-dimensional (2D) clinical photographs, panoramic and cephalometric radiographs, and dental casts. The 3D facial scans were compared to scans of a healthy control group and analyzed using a spatially dense geometric morphometric approach. Cephalometric radiographs were digitally traced, and measurements were compared to existing standards. Occlusal and dental features were studied on dental casts and panoramic radiographs. Interestingly, a general trend of facial hypoplasia in the lower part of the face could be evidenced with the 3D facial analysis in children with 22q11.2DS compared to controls. Cephalometric analysis confirmed a dorsal position of the mandible to the maxilla in 2D and showed an enlarged cranial base angle. Measurements for occlusion did not differ significantly from standards. Despite individual variability, we observed a retruded lower part of the face as a common feature, and we also found a significantly higher prevalence of tooth agenesis in our cohort of 20 children with 22q11.2DS (20%). Furthermore, 3D facial surface scanning proved to be an important noninvasive, diagnostic tool to investigate external features and the underlying skeletal pattern. [ABSTRACT FROM AUTHOR]

Genome sequencing raises new ethical challenges. Decoding the genome produces new forms of diagnostic and prognostic information; however, the information is often difficult to interpret. The connection between most genetic variants and their phenotypic manifestations is not understood. This scenario is particularly true for disorders that are not associated with an autosomal genetic variant. The analytic uncertainty is compounded by moral uncertainty about how, exactly, the results of genomic testing should influence clinical decisions. In this Ethics Rounds, we present a case in which genomic findings seemed to play a role in deciding whether a patient was to be listed as a transplant candidate. We then asked experts in bioethics and cardiology to discuss the implications of such decisions. Genome sequencing raises new ethical challenges. Decoding the genome produces new forms of diagnostic and prognostic information; however, the information is often difficult to interpret. The connection between most genetic variants and their phenotypic manifestations is not understood. This scenario is particularly true for disorders that are not associated with an autosomal genetic variant. The analytic uncertainty is compounded by moral uncertainty about how, exactly, the results of genomic testing should influence clinical decisions. In this Ethics Rounds, we present a case in which genomic findings seemed to play a role in deciding whether a patient was to be listed as a transplant candidate. We then asked experts in bioethics and cardiology to discuss the implications of such decisions. [ABSTRACT FROM AUTHOR]

The patients with DiGeorge syndrome (DGS), caused by deletion containing dozens of genes in chromosome 22, often carry cardiovascular problem and hearing loss associated with chronic otitis media. Inside the deletion region, a transcription factor TBX1 was highly suspected. Furthermore, similar DGS phenotypes were found in the Tbx1 heterozygous knockout mice. Using ENU-induced mutagenesis and G1 dominant screening strategy, here we identified a nonsynonymous mutation p.W118R in T-box of TBX1, the DNA binding domain for transcription activity. The mutant mice showed deficiency of inner ear functions, including head tossing and circling, plus increased hearing threshold determined by audiometry. Therefore, our result further confirms the pathogenic basis of Tbx1 in DGS, points out the crucial role of DNA binding activity of TBX1 for the ear function, and provides additional animal model for studying the DGS disease mechanisms. [ABSTRACT FROM AUTHOR]

The behavioural phenotype of 22q11.2 deletion syndrome syndrome (22q11DS), one of the most common human multiple anomaly syndromes, frequently includes intellectual disability (ID) together with high risk of diagnosis of psychotic disorders including schizophrenia. Candidate cognitive endophenotypes include problems with retrieval of contextual information from memory and in executive control and focussing of attention. 22q11DS may offer a model of the relationship between ID and risk of psychiatric disorder. This paper reviews research on the relationship between the cognitive phenotype and the development of psychiatric disorders in 22q11DS. Aspects of cognitive function including verbal I.Q., visual memory, and executive function, are associated with mental health outcome in people with 22q11DS. This relationship may result from a common neurobiological basis for the cognitive difficulties and psychiatric disorders. Some of the cognitive difficulties experienced by people with 22q11DS, especially in attention, memory retrieval, and face processing, may, however, in themselves constitute risk factors for development of hallucinations and paranoid delusions. Future research into factors leading to psychiatric disorder in people with 22q11DS should include assessment of social and psychological factors including life events, symptoms associated with trauma, attachment, and self-esteem, which together with cognitive risk factors may mediate mental health outcome. [ABSTRACT FROM AUTHOR]

Background and Objectives. The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the post-childhood period. Methods. A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. Results. During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. Conclusion. Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS. [ABSTRACT FROM AUTHOR]

The chromosome 22q11.2 region has long been implicated in genomic diseases. Some genomic regions exhibit numerous low copy repeats with high identity in which they provide increased genomic instability and mediate deletions and duplications in many disorders. DiGeorge Syndrome is the most common deletion syndrome and reciprocal duplications could be occurring in half of the frequency of microdeletions. We described five patients with phenotypic variability that carries deletions or reciprocal duplications at 22q11.2 detected by Chromosomal Microarray Analysis. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had clinical indication to global developmental delay and a normal karyotype. We observed in our study three microdeletions and two microduplications in 22q11.2 region with variable intervals containing known genes and unstudied transcripts as well as the LCRs that are often flanking and within this genomic rearrangement. The identification of these variants is of particular interest because it may provide insight into genes or genomic regions that are crucial for specific phenotypic manifestations and are useful to assist in the quest for understanding the mechanisms subjacent to genomic deletions and duplications. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms 'proximal', 'nested', 'distal', and 'atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS. [ABSTRACT FROM AUTHOR]

DiGeorge syndrome (DGS) is one of the most frequently seen chromosomal abnormalities. The major genetic cause of DGS is a microdeletion on chromosome 22q11.2. Majority of the cases are diagnosed during their childhood. DGS is rarely considered and diagnosed in adulthood. Herein, we report the first case of a patient with DGS and azoospermia in the literature. Our patient was a 35-year-old male with mild dysmorphic features, hypernasal voice, mental retardation, and azoospermia. His laboratory tests and echocardiographic assessments were normal. Clinical clues to DGS were hypernasal voice and dysmorphic features with mild mental retardation. The diagnosis of DGS was confirmed by fluorescence in situ hybridization (FISH). Negative effects of cognitive disorders on reproductivity are already known; however, we haven't find any studies in the literature that evaluated infertile patients with DGS using semen analysis, apart from these potential unfavourable effectc of cognitive disorders. Coexistence of DGS and azoospermia may be completely coincidental, but azoospermia can be also one of the unknown clinical features of this syndrome. Many patients with a mild phenotype of DGS may be underdiagnosed. DGS should be considered in adults who have mental, behavioral, or psychiatric disorders with mild dysmorphic features, even in the absence of classical features. [ABSTRACT FROM AUTHOR]

T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbxl heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbxl. We found that Gbx2 expression is down-regulated in Tbx1+/- embryos and is restored to normal levels in Tbx1+/-;Trp53+/- embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1+/-;Trp53+/- embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically. [ABSTRACT FROM AUTHOR]

Purpose: Population-based newborn screening using T-cell receptor excision circles (TREC) identifies infants with severe T-lymphopenia, seen in severe combined immunodeficiencies (SCID), but also infants with the 22q11 deletion syndrome (22q11DS). Methods for analysis of kappa-deleting recombination excision circles (KREC) help identifying infants with B-lymphopenia. We aimed to evaluate the occurrence of abnormal TREC or KREC newborn screening results in 22q11DS patients and assessed the clinical relevance of abnormal screening reports. Methods: Simultaneous TREC and KREC analysis was performed on stored original Guthrie cards. Patients with abnormal screening reports were compared to patients with normal reports, regarding lymphocyte counts and clinical severity, obtained by retrospective analysis of medical charts. Results: Of 48 included patients, nine (19 %) had abnormal TREC copy numbers. All 22q11DS patients with abnormal TRECs had CD3+ T-lymphopenia at the time of diagnosis, but only one patient had the complete DiGeorge syndrome. Identified 22q11DS patients with abnormal TREC copy numbers showed significantly lower CD8+ T-lymphocytes at time-of-diagnosis and were significantly more prone to viral infections, compared to 22q11DS patients with normal TREC copy numbers. All 22q11DS patients showed KREC copies within the normal range. Conclusions: In this retrospective study a high proportion of 22q11DS patients were identified by TREC-based newborn screening. Although only one of them had the complete DiGeorge syndrome with no T-lymphocytes, all of them had T-lymphopenia and most of them had recurrent viral infections, as well as other medical problems, warranting early recognition of the syndrome. [ABSTRACT FROM AUTHOR]

Cleavage of microRNAs and mRNAs by Drosha and its cofactor Pasha/DGCR8 is required for animal development, but whether these proteins also have independent roles in development has been unclear. Known phenotypes associated with loss of either one of these two proteins are very similar and consistent with their joint function, even though both cofactors are involved with additional distinct RNA biogenesis pathways. Here, we report clear phenotypic differences between drosha and pasha/dgcr8 null alleles in two postembryonic lineages in the Drosophila brain: elimination of pasha/dgcr8 leads to defects that are not shared by drosha null mutations in the morphology of gamma neurons in the mushroom body lineage, as well as many neurons in the anterodorsal projection neuron lineage. These morphological defects are not detected in neurons that are genetically depleted of two additional microRNA pathway components, dicer-1 and argonaute1, indicating that they are not due to loss of microRNA activity. They are, however, phenocopied by a newly identified recessive gain-of-function allele in drosha that probably interferes with the microRNA independent functions of Pasha/DGCR8. These data therefore identify a general Drosha-independent DGCR8/Pasha pathway that promotes proper morphology in multiple neuronal lineages. Given that reduction of human DGCR8/Pasha may contribute to the cognitive and behavioral characteristics of DiGeorge syndrome patients, disruption of this newly described pathway could underlie human neurological disease. [ABSTRACT FROM AUTHOR]

Background 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion. Methods Thirty-two 22q11.2DS subjects among 26 families were enrolled. Results Second generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P < 0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability. Conclusions Second generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11DS) results from a hemizygous microdeletion on chromosome 22 and is characterized by extensive phenotypic variability. Penetrance of signs, including congenital heart, craniofacial, and neurobehavioral abnormalities, varies widely and is not well correlated with genotype. The three-dimensional structure of the genome may help explain some of this variability. The physical interaction profile of a given gene locus with other genetic elements, such as enhancers and co-regulated genes, contributes to its regulation. Thus, it is possible that regulatory interactions with elements outside the deletion region are disrupted in the disease state and modulate the resulting spectrum of symptoms. COMT, a gene within the commonly deleted ~3 Mb region has been implicated as a contributor to the neurological features frequently found in 22q11DS patients. We used this locus as bait in a 4C-seq experiment to investigate genome-wide interaction profiles in B lymphocyte and fibroblast cell lines derived from both 22q11DS and unaffected individuals. All normal B lymphocyte lines displayed local, conserved chromatin looping interactions with regions that are lost in atypical and distal deletions, which may mediate similarities between typical, atypical, and distal 22q11 deletion phenotypes. There are also distinct clusterings of cis interactions based on disease state. We identified regions of differential trans interactions present in normal, and lost in deletion-carrying, B lymphocyte cell lines. This data suggests that hemizygous chromosomal deletions such as 22q11DS can have widespread effects on chromatin organization, and may contribute to the inherent phenotypic variability. [ABSTRACT FROM AUTHOR]

Background Genomic rearrangements usually involve one of the two chromosome homologues. Homozygous microdeletion/duplication is very rare. The chromosome 22q11.2 region is prone to recurrent rearrangements due to the presence of low-copy repeats. A common 3 Mb microdeletion causes the well-characterised DiGeorge syndrome (DGS). The reciprocal duplication is associated with an extremely variable phenotype, ranging from apparently normal to learning disabilities and multiple congenital anomalies. Methods and results We describe duplications of the DGS region on both homologues in five patients from three families, detected by array CGH and confirmed by both fluorescence in situ hybridisation and single nucleotide polymorphism arrays. The proband in the first family is homozygous for the common duplication; one maternally inherited and the other a de novo duplication that was generated by nonallelic homologous recombination during spermatogenesis. The 22q11.2 duplications in the four individuals from the other two families are recurrent duplications on both homologues, one inherited from the mother and the other from the father. The phenotype in the patients with a 22q11.2 tetrasomy is similar to the features seen in duplication patients, including cognitive deficits and variable congenital defects. Conclusions Our studies that reveal phenotypic variability in patients with four copies of the 22q11.2 genomic segment, demonstrate that both inherited and de novo events can result in the generation of homozygous duplications, and further document how multiple seemingly rare events can occur in a single individual. [ABSTRACT FROM AUTHOR]

Abstract: To illustrate the impact developmental biology and genetics have already had on the clinical management of the million infants born worldwide each year with CHD, we have chosen three stories which have had particular relevance for pediatric cardiologists, cardiothoracic surgeons, cardiac anesthesiologists, and cardiac nurses. First, we show how Margaret Kirby’s finding of the unexpected contribution of an ectodermal cell population – the cranial neural crest – to the aortic arch arteries and arterial pole of the embryonic avian heart provided a key impetus to the field of cardiovascular patterning. Recognition that a majority of patients affected by the neurocristopathy DiGeorge syndrome have a chromosome 22q11 deletion, have also spurred tremendous efforts to characterize the molecular mechanisms contributing to this pathology, assigning a major role to the transcription factor Tbx1. Second, synthesizing the work of the last two decades by many laboratories on a wide gamut of metazoans (invertebrates, tunicates, agnathans, teleosts, lungfish, amphibians, and amniotes), we review the >20 major modifications and additions to the ancient circulatory arrangement composed solely of a unicameral (one-chambered), contractile myocardial tube and a short proximal aorta. Two changes will be discussed in detail – the interposition of a second cardiac chamber in the circulation and the septation of the cardiac ventricle. By comparing the developmental genetic data of several model organisms, we can better understand the origin of the various components of the multicameral (multi-chambered) heart seen in humans. Third, Martina Brueckner’s discovery that a faulty axonemal dynein was responsible for the phenotype of the iv/iv mouse (the first mammalian model of human heterotaxy) focused attention on the biology of cilia. We discuss how even the care of the complex cardiac and non-cardiac anomalies seen in heterotaxy syndrome, which have long seemed impervious to advancements in surgical and medical intensive care, may yet yield to strategies grounded in a better understanding of the cilium. The fact that all cardiac defects seen in patients with full-blown heterotaxy can also be seen in patients without obvious laterality defects hints at important roles for ciliary function not only in left–right axis specification but also in cardiovascular morphogenesis. These three developmental biology stories illustrate how the remaining unexplained mortality and morbidity of congenital heart disease can be solved. [Copyright &y& Elsevier]

22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20-25% of individuals with a chromosome 22q11.2 microdeletion. From the initial discovery of the syndrome, associated developmental delays made it clear that changes in brain development were a key part of the expression. Once patients were followed through childhood into adult years, further neurobehavioural phenotypes became apparent, including a changing cognitive profile, anxiety disorders and seizure diathesis. The variability of expression is as wide as for the myriad physical features associated with the syndrome, with the addition of evolving phenotype over the developmental trajectory. Notably, variability appears unrelated to length of the associated deletion. Several mouse models of the deletion have been engineered and are beginning to reveal potential molecular mechanisms for the cognitive and behavioural phenotypes observable in animals. Both animal and human studies hold great promise for further discoveries relevant to neurodevelopment and associated cognitive, behavioural and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract: Tbx1 is the candidate gene of DiGeorge syndrome and is required in humans and mice for the development of the cardiac outflow tract (OFT) and aortic arch arteries. Loss of function mutants present with reduced cell proliferation and premature differentiation of cardiac progenitor cells of the second heart field (SHF). Tbx1 regulates Fgf8 expression hence the hypothesis that the proliferation impairment may contribute to the heart phenotype of mutants. Here we show that forced Fgf8 expression modifies and partially rescues the OFT septation defects of Tbx1 mutants but only if there is some residual expression of Tbx1. This genetic experiment suggests that Tbx1, directly or indirectly, affects tissue response to Fgf8. Indeed, Tbx1 −/− mouse embryonic fibroblasts were unable to respond to Fgf8 added to the culture media and showed defective response of Erk1/2 and Rsk1. Our data suggest a coordinated pathway modulating Fgf8 ligand expression and tissue response to it in the SHF. [ABSTRACT FROM AUTHOR]

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age. [ABSTRACT FROM AUTHOR]

Summary: Velo-cardio-facial syndrome (VCFS) is a genetic disorder that is common but often variable in its expression. Several key organ systems are most often affected, including the craniofacial skeleton and soft tissues. Identification of the associated facial features will aid in the improved detection of patients. This review aims to highlight the approaches to facial analysis that are essential to the detection of the facial dysmorphisms in velo-cardio-facial syndrome, many of which may be subtle. [Copyright &y& Elsevier]

We report a case of DiGeorge-like syndrome in which immunodeficiency coexisting with juvenile idiopathic arthritis, congenital heart disease, delay in emergence of language and in motor milestones, feeding and growing problems, enamel hypoplasia, mild skeletal anomalies, and facial dysmorphisms are associated with no abnormalities found on genetic tests. [ABSTRACT FROM AUTHOR]

Velo-cardio-facial syndrome is one of the names that has been attached to one of the most common multiple anomaly syndromes in humans. The labels DiGeorge sequence, 22q11 deletion syndrome, conotruncal anomalies face syndrome, CATCH 22, and Sedlačková syndrome have all been attached to the same disorder. Velo-cardio-facial syndrome has an expansive phenotype with more than 180 clinical features described that involve essentially every organ and system. The syndrome has drawn considerable attention because a number of common psychiatric illnesses are phenotypic features including attention deficit disorder, schizophrenia, and bipolar disorder. The expression is highly variable with some individuals being essentially normal at the mildest end of the spectrum, and the most severe cases having life-threatening and life-impairing problems. The syndrome is caused by a microdeletion from chromosome 22 at the q11.2 band. Although the large majority of affected individuals have identical 3 megabase deletions, less than 10% of cases have smaller deletions of 1.5 or 2.0 megabases. The 3 megabase deletion encompasses a region containing 40 genes. The syndrome has a population prevalence of approximately 1:2,000 in the United States, although incidence is higher. Although initially a clinical diagnosis, today velo-cardio-facial syndrome can be diagnosed with extremely high accuracy by fluorescence in situ hybridization and several other laboratory techniques. Clinical management is age dependent with acute medical problems such as congenital heart disease, immune disorders, feeding problems, cleft palate, and developmental disorders occupying management in infancy and preschool years. Management shifts to cognitive, behavioral, and learning disorders during school years, and then to the potential for psychiatric disorders including psychosis in late adolescence and adult years. Although the majority of people with velo-cardio-facial syndrome do not develop psychosis, the risk for severe psychiatric illness is 25 times higher for people affected with velo-cardio-facial syndrome than that of the general population. Therefore, interest in understanding the nature of psychiatric illness in the syndrome remains strong. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:3–10. [ABSTRACT FROM AUTHOR]

Several recurrent, constitutional genomic disorders are present on chromosome 22q. These include the translocations and deletions associated with DiGeorge and velocardiofacial syndrome and the translocations that give rise to the recurrent t(11;22) supernumerary der(22) syndrome (Emanuel syndrome). The rearrangement breakpoints on 22q cluster around the chromosome-specific segmental duplications of proximal 22q11, which are involved in the etiology of these disorders. While the deletions are the result of nonallelic homologous recombination (NAHR) between low copy repeats or segmental duplications within 22q11, the t(11;22) is the result of rearrangement between palindromic AT-rich repeats on 11q and 22q. Here we describe the mechanisms responsible for these recurrent rearrangements, discuss the recurrent deletion endpoints that are the result of NAHR between chromosome 22q specific low copy repeats as well as present current diagnostic approaches to deletion detection. [ABSTRACT FROM AUTHOR]

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), the most common micro-deletion disorder in humans, is characterized by craniofacial, parathyroid, and thymic defects as well as cardiac outflow tract malformations. Most patients have a similar hemizygous 3 million base pair deletion on 22q11.2. Studies in mouse have shown that Tbx1, a T-box containing transcription factor present on the deleted region, is likely responsible for the etiology of the syndrome. Furthermore, mutations in TBX1 have been found in rare non-deleted patients. Despite having the same sized deletion, most VCFS/DGS patients exhibit significant clinical variability. Stochastic, environmental and genetic factors likely modify the phenotype of patients with the disorder. Here, we review mouse genetics studies, which may help identify possible genetic modifiers for the physical malformations in VCFS/DGS. [ABSTRACT FROM AUTHOR]