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BACKGROUND: The 2q31 deletion results in a distinct phenotype characterized by varying degrees of developmental delay, short stature, facial dysmorphism, and variable limb defects. Dysmorphic features include microcephaly, downslanting palpebral fissures, a long and flat philtrum, micrognathia, and dysplastic, low-set ears. To date, comparative genomic hybridization has identified this deletion in 38 patients. Consequently, additional patients with comprehensive clinical data are required to fully understand the spectrum of clinical manifestation associated with a deletion in the 2q31 cytoband. CASE PRESENTATION: We present the case of an 8-year-old female patient with clinical features of velocardiofacial syndrome, which include facial dysmorphism, congenital heart disease (persistent truncus arteriosus and ostium secundum-type atrial septal defect), and a seizure syndrome. Array comparative genomic hybridization revealed a non-continous deletion spanning cytobands 2q31.1-to 2q31.3, confirming a diagnosis of 2q31 microdeletion syndrome. The patient has undergone supportive therapies for swallowing and speech. Additionally, we provide a review of the literature on previous cases to give context. CONCLUSION: In this report, we present the first documented case of a complex, discontinuous deletion spanning in the 2q31-2q32 regions. This case contributes to our understanding of the phenotypic and mutational spectrum observed in individuals with deletions in these cytobands. It underscores the significance of employing high-resolution techniques and comprenhensive analysis in diagnosing patients with complex phenotypes. Such approaches are crucial for differentiating this condition from more common microdeletion syndromes, such as the 22q11 deletion syndrome.

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Background: 20q11.2 microdeletion syndrome [ORPHA: 444051] is a rare disease, since 16 patients have been reported in literature worldwide. Prevalence ratio is < 1:1,000,000 individuals. Haploinsufficiency on GDF5, SAMHD1 and EPB41L1 genes is important due to phenotypic manifestations in patients. Clinical features can be grouped into craniofacial abnormalities, limb abnormalities, neurological and perinatal disorders. The aim of this report is to present a clinical case of 20q11.21-q11.23 microdeletion, to describe clinical manifestations found, to compare them with features reported in literature, and to contribute to the phenotypic spectrum expansion. Clinical case: 5-year-old female patient who presented hypotonia, psychomotor retardation, microcephaly, facial dysmorphia, pectus excavatum, thoracolumbar scoliosis, right hip subluxation, camptodactyly and clinodactyly. Karyotype test was normal and SNP microarray test reported deletion of chromosomal region 20q11.21-q11.23. Conclusions: It was presented a 20q11.2 microdeletion syndrome confirmed case that shares the features reported in literature, in addition to previously unreported features, such as blepharoptosis, pectus excavatum, scoliosis and hip dysplasia. Interdisciplinary management is important to improve the patient's condition (in her 3 spheres), in order to achieve her best possible health status.

Introducción: el síndrome de microdeleción 20q11.2 [ORPHA: 444051] es una enfermedad rara, pues se han reportado 16 casos a nivel mundial. Su prevalencia se estima en < 1:1,000,000 de nacidos vivos. Induce haploinsuficiencia en los genes GDF5, SAMHD1 y EPB41L1, los cuales son de importancia clínica por las manifestaciones fenotípicas. Se caracteriza por anomalías craneofaciales, anomalías de extremidades, alteraciones neurológicas y perinatales. El objetivo de este reporte es presentar un caso de microdeleción 20q11.21-q11.23, describir las manifestaciones clínicas encontradas, compararlo con lo reportado en la literatura y colaborar en la ampliación del espectro fenotípico. Caso clínico: paciente del sexo femenino de 5 años que presentó hipotonía, retraso psicomotor, microcefalia, dismorfias faciales, pectus excavatum, escoliosis toracolumbar, subluxación de cadera derecha, camptodactilia y clinodactilia. La prueba de cariotipo se reportó sin alteraciones y el ensayo de microarreglo de polimorfismos de un nucleótido (SNP) reportó deleción de la región cromosómica 20q11.21-q11.23. Conclusiones: se presentó un caso confirmado de síndrome de microdeleción 20q11.2 que comparte las características reportadas en la literatura, además de características no reportadas previamente, como ptosis palpebral, pectus excavatum, escoliosis y displasia del desarrollo de cadera. Es importante el manejo interdisciplinario para buscar mejoría en la condición de la paciente (en sus 3 esferas), a fin de alcanzar el mejor estado de salud posible.

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BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes. RESULTS: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls. CONCLUSIONS: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.

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The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical ≈3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life.

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Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the MIF gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome.

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22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

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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.

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The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.

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The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

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PURPOSE: The purpose of this study was to describe the deep phenotype of congenital corneal opacities (CCO) in patients with 22q11.2 deletion syndrome (22q11.2 DS) and to identify putative regions or genes that could explain the CCO. METHODS: A retrospective chart review was conducted to identify patients with 22q11.2 DS seen in the ophthalmology clinic of a tertiary referral children's hospital. Thirty patients were identified, with molecular confirmation. Twenty-six did not show structural anterior segment anomalies aside from posterior embryotoxon (n = 4), whereas 4 had bilateral CCO, of which 3 had preoperative images. We reviewed medical, operative, and pathology reports; anterior segment optical coherence tomography; high-frequency ultrasound; histopathologic slides; and genetic testing. To identify putative genes responsible for CCO, chromosomal breakpoints in patients with and without CCO were compared. RESULTS: In the 3 patients with preoperative imaging and CCO, a pattern of paracentral corneal opacification with central clearing accompanied by iridocorneal or keratolenticular adhesions was observed. Anterior segment optical coherence tomography and histopathologic images showed central stromal thinning with a residual structure consistent with Descemet membrane. One patient presented at birth with unilateral corneal perforation, suggestive of likely stromal thinning. A comparison of the breakpoints across all cases failed to reveal unique regions or genes in patients with CCO. CONCLUSIONS: 22q11.2 DS can rarely be associated with CCO. We describe a consistent pattern of central clearing related to posterior stromal thinning, with or without ICA/KLA. Possible candidate genes for corneal opacification in 22q11.2 DS remain elusive.

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Noonan syndrome (NS) is caused by pathogenic variants in genes involved in the RAS/MAPK pathway. On the other hand, 22q11.2 Deletion Syndrome (22q11.2DS) is caused by heterozygous microdeletion on chromosome 22q11.2. The clinical characteristics of both syndromes are expected to be relatively distinct, and, in fact, there is only one report of these syndromes occurring together, but on daily clinical practice and especially in early childhood phenotypes may overlap. In this study, we describe a patient with NS and 22q11.2DS features harboring a heterozygous 2.54 Mb deletion of chromosome 22q11.2 and a variant in LZTR1, c.1531G > A p.(Val511Met). In 1993, Wilson et al reported a patient with both 22q11.2DS and NS, proposing that probably more than one gene is deleted in the proband and that one of the deleted genes is responsible for Noonan's phenotype. In our patient, one of the deleted genes within the 22q11.2 region was the LZTR1 gene which was associated with NS in 2015. This case also highlights the importance of the long-term patients' follow-up to detect evolutionary changes that may appear in the phenotype and alerts clinicians of the co-occurrence of two syndromes that may manifest over time.

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OBJECTIVES: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome and has a multisystemic presentation including gastrointestinal features that have not yet been fully described. Our aim was to examine lifetime gastrointestinal problems in a large cohort of patients with 22q11.2DS. METHODS: All patients followed in the 22q and You Center at the Children's Hospital of Philadelphia (n = 1421) were retrospectively screened for: 1) age ≥ 17 years, 2) documented chromosomal microdeletion within the 22q11.2 LCR22A-LCR22D region, and 3) sufficient clinical data to characterize the adult gastrointestinal phenotype. Gastrointestinal problems in childhood, adolescence, and adulthood were summarized. Statistical association testing of symptoms against other patient characteristics was performed. RESULTS: Included patients (n = 206; 46% female; mean age, 27 years; median follow-up, 21 years) had similar clinical characteristics to the overall cohort. Genetic distribution was also similar, with 96% having deletions including the critical LCR22A-LCR22B segment (95% in the overall cohort). Most patients experienced chronic gastrointestinal symptoms in their lifetime (91%), but congenital gastrointestinal malformations (3.5%) and gastrointestinal autoimmune diseases (1.5%) were uncommon. Chronic symptoms without anatomic or pathologic abnormalities represented the vast burden of illness. Chronic symptoms in adulthood are associated with other chronic gastrointestinal symptoms and psychiatric comorbidities ( P < 0.01) but not with deletion size or physiologic comorbidities ( P > 0.05). One exception was increased nausea/vomiting in hypothyroidism ( P = 0.002). CONCLUSIONS: Functional gastrointestinal disorders (FGIDs) are a common cause of ill health in children and adults with 22q11.2DS. Providers should consider screening for the deletion in patients presenting with FGIDs and associated comorbidities such as neuropsychiatric illness, congenital heart disease, and palatal abnormalities.

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BACKGROUND: Some syndromes have specific and easily recognizable features, while others may be more complex to identify and may present different phenotypic manifestations, for example. An etiological diagnosis is important to understand the nature of the disease, to establish the prognosis and to start the treatment, allowing the inclusion of patients in society and reducing the financial cost of such diseases. OBJECTIVE: The initial proposal of this study was cytogenetic screening for the detection of the 22q11.2 deletion syndrome in consecutive newborns and infants with congenital heart disease using the multiplex ligation-dependent probe amplification (MLPA) technique. Therefore, throughout our research, other genomic alterations were identified in these cardiac patients. Thus, our objective was extended to investigate these other cytogenetic alterations. METHODS: We investigated 118 neonates with congenital heart diseases born consecutively during one year using the MLPA technique. RESULTS: The MLPA technique allowed the detection of 22q11.2DS in 10/118 patients (8.5%). Other genomic alterations were also identified in 6/118 patients (5%): 1p36 del, 8p23 del (2 cases), 7q dup, 12 dup and 8q24 dup. CONCLUSION: This study highlights the relevance of detecting genomic alterations that are present in newborns and infants with congenital cardiac diseases using cytogenomic tools.

FUNDAMENTO: Algumas síndromes têm características específicas e facilmente reconhecíveis, enquanto outras podem ser mais complexas de se identificar e podem apresentar diferentes manifestações fenotípicas, por exemplo. Um diagnóstico etiológico é importante para entender a natureza da doença, para estabelecer o prognóstico e para começar o tratamento, permitindo a inclusão de pacientes na sociedade e reduzindo o custo financeiro dessas doenças. OBJETIVO: A proposta inicial deste estudo foi a triagem citogenética para detectar a síndrome de deleção 22q11.2 (SD22q11.2) em recém-nascidos e crianças com doença cardíaca congênita utilizando a técnica da amplificação multiplex de sondas dependente de ligação (MLPA). Assim, por meio da pesquisa, outras mudanças genômicas foram identificadas nesses pacientes cardíacos. Nosso objetivo se estendeu a investigar essas outras mudanças citogenéticas. MÉTODOS: Investigamos 118 recém-nascidos com doenças cardíacas congênitas nascidos consecutivamente durante um ano, utilizando a técnica da MLPA. RESULTADOS: A técnica da MLPA permitiu a detecção da SD22q11.2 em 10/118 pacientes (8,5%). Outras alterações genômicas foram identificadas em 6/118 pacientes (5%): 1p36 del, 8p23 del (2 casos), 7q dup, 12 dup e 8q24 dup. CONCLUSÃO: Este estudo ressalta a relevância da detecção de alterações genômicas que estão presentes em recém-nascidos e crianças com doenças cardíacas congênitas por meio de ferramentas citogenômicas.

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BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a rare disease with an important characteristic-clinical heterogeneity. The diversity of organs, regions, and systems of the body that can be affected requires periodic updating of health professionals so that they can recognize these clinical signs as belonging to 22q11.2DS. Updated professionals are equally important for the appropriate and timely clinical management of individuals with a positive diagnosis. In this context, this article aimed to map and analyze the access to healthcare for individuals with 22q11.2DS until the moment of diagnosis. RESULTS: We analyzed the clinical data of 111 individuals with 22q11.2DS registered in the Brazilian Database on Craniofacial Anomalies (BDCA) from 2008 to 2020. In this study, individuals were diagnosed at a median age of 9 years (mean = 9.7 years). Before the genetic investigation, they accessed 68.75% of the internationally recommended evaluations available at BDCA. Recurrent 22q11.2DS clinical manifestations such as delayed neuropsychomotor development, lip and/or palate defects, cardiac malformation and/or hematological/immunological alteration co-occurred in at least 72.06% of individuals. Cardiac malformation was the only clinical alteration that lowered the median diagnostic age, corresponding to 6.5 years of age with a cardiac malformation versus 11 years of age without one (p = 0.0006). CONCLUSIONS: In Brazil, 22q11.2 DS is under-recognized, and early diagnosis and management of affected individuals are still a distant reality. In this sense, 22q11.2 DS suspicion followed by the elimination of obstacles for its diagnosis confirmation is essential to increase life expectancy and improve the quality of life of these individuals in Brazil.

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Resumo Fundamento Algumas síndromes têm características específicas e facilmente reconhecíveis, enquanto outras podem ser mais complexas de se identificar e podem apresentar diferentes manifestações fenotípicas, por exemplo. Um diagnóstico etiológico é importante para entender a natureza da doença, para estabelecer o prognóstico e para começar o tratamento, permitindo a inclusão de pacientes na sociedade e reduzindo o custo financeiro dessas doenças. Objetivo A proposta inicial deste estudo foi a triagem citogenética para detectar a síndrome de deleção 22q11.2 (SD22q11.2) em recém-nascidos e crianças com doença cardíaca congênita utilizando a técnica da amplificação multiplex de sondas dependente de ligação (MLPA). Assim, por meio da pesquisa, outras mudanças genômicas foram identificadas nesses pacientes cardíacos. Nosso objetivo se estendeu a investigar essas outras mudanças citogenéticas. Métodos Investigamos 118 recém-nascidos com doenças cardíacas congênitas nascidos consecutivamente durante um ano, utilizando a técnica da MLPA. Resultados A técnica da MLPA permitiu a detecção da SD22q11.2 em 10/118 pacientes (8,5%). Outras alterações genômicas foram identificadas em 6/118 pacientes (5%): 1p36 del, 8p23 del (2 casos), 7q dup, 12 dup e 8q24 dup. Conclusão Este estudo ressalta a relevância da detecção de alterações genômicas que estão presentes em recém-nascidos e crianças com doenças cardíacas congênitas por meio de ferramentas citogenômicas.

Abstract Background Some syndromes have specific and easily recognizable features, while others may be more complex to identify and may present different phenotypic manifestations, for example. An etiological diagnosis is important to understand the nature of the disease, to establish the prognosis and to start the treatment, allowing the inclusion of patients in society and reducing the financial cost of such diseases. Objective The initial proposal of this study was cytogenetic screening for the detection of the 22q11.2 deletion syndrome in consecutive newborns and infants with congenital heart disease using the multiplex ligation-dependent probe amplification (MLPA) technique. Therefore, throughout our research, other genomic alterations were identified in these cardiac patients. Thus, our objective was extended to investigate these other cytogenetic alterations. Methods We investigated 118 neonates with congenital heart diseases born consecutively during one year using the MLPA technique. Results The MLPA technique allowed the detection of 22q11.2DS in 10/118 patients (8.5%). Other genomic alterations were also identified in 6/118 patients (5%): 1p36 del, 8p23 del (2 cases), 7q dup, 12 dup and 8q24 dup. Conclusion This study highlights the relevance of detecting genomic alterations that are present in newborns and infants with congenital cardiac diseases using cytogenomic tools.

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The 22q11.2 Deletion Syndrome has significant impact on brain and behavior, with about 25% of individuals developing schizophrenia. The condition offers a model for prospective studies on the emergence of psychosis and advancing mechanistic hypotheses on gene-environment interactions, with magnified power for examining genome-phenome association. Here, we highlight findings that build on the International 22q11.2 Brain and Behavior Consortium and relate to several key domains in the study of psychosis-risk and schizophrenia. We examine neurocognition, olfaction and neuroimaging data that indicate similar impairment patterns in this rare syndrome and idiopathic presentation of schizophrenia. We conclude that the converging paradigms, studying psychosis dimensionally in rare and common variants samples, provide complementary approaches that will propel precision medicine in psychiatry.

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Congenital heart disease (CHD) and palatal anomalies (PA), are among the most common characteristics of 22q11.2 deletion syndrome (22q11.2DS), but they show incomplete penetrance, suggesting the presence of additional factors. The 22q11.2 deleted region contains nuclear encoded mitochondrial genes, and since mitochondrial function is critical during development, we hypothesized that changes in the mitochondrial DNA (mtDNA) could be involved in the intrafamilial variability of CHD and PA in cases of maternally inherited 22q11.2DS. To investigate this, we studied the transmission of heteroplasmic mtDNA alleles in seventeen phenotypically concordant and discordant mother-offspring 22q11.2DS pairs. We sequenced their mtDNA and identified 26 heteroplasmic variants at >1% frequency, representing 18 transmissions. The median allele frequency change between a mother and her child was twice as much, with a wider distribution range, in PA discordant pairs, p-value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, p-value = 0.441 (9 vs. 9). Only the variant m.9507T>C was considered to be pathogenic, but it was unrelated to the structural phenotypes. Our study is novel, yet our results are not consistent with mtDNA variation contributing to PA or CHD in 22q11.2DS. Larger cohorts and additional factors should be considered moving forward.

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This article reports the present situation of Brazilian health care in genetics for Orofacial Cleft (OFC) and 22q11.2 Deletions Syndrome (22q11.2 DS) based on research conducted by Brazil's Craniofacial Project (BCFP). Established in 2003, BCFP is a voluntary and cooperative network aiming to investigate the health care of people with these diseases and other craniofacial anomalies. The initiatives and research results are presented in four sections: (a) a comprehensive report of the Brazilian public health system in craniofacial genetics; (b) multicentric studies developed on OFC and 22q11.2 DS; (c) education strategies focused on addressing these conditions for both population and health-care professionals; and (d) the nosology through the Brazilian Database on Craniofacial Anomalies (BDCA). Since 2006, BDCA uses a standardized method with detailed clinical data collection, which allows for conducting studies on nosology, genotype-phenotype correlations, and natural history; data can also contribute to public policies. Currently, the BDCA stores data on 1,724 individuals, including 1,351 (78.36%) who were primarily admitted due to OFC and 373 (21.63%) with clinical suspicion of 22q11.2 DS. Chromosomal abnormalities/genomic imbalances were represented by 92/213 (43.19%) individuals with syndromic OFC, including 43 with 22q11.2 DS, which indicates the need for chromosomal microarray analysis in this group. The nosologic diversity reinforces that monitoring clinical is the best strategy for etiological investigation. BCFP's methodology has introduced the possibility of increasing scientific knowledge and genetic diagnosis of OFC and 22q11.2 DS to in turn improve health care and policies for this group of diseases.

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Abstract Congenital heart defects are the most common birth defects and the leading cause of mortality in the first year of life. It is well known that the 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and that congenial heart diseases (CHDs) are one of the most common phenotypic manifestations. However, it should be noted that the 22q11 deletion was also found in a significant number of patients with isolated CHD. The 22q11DS phenotype may include cardiovascular anomalies, palatal abnormalities, nasal voice, immune deficiency, endocrine dysfunctions, a varying degree of cognitive deficits and intellectual disabilities, velopharyngeal insufficiency, and characteristic craniofacial dysmorphism. This condition affects about 1 in 4,000 live births, making 22q11DS the most common microdeletion syndrome in humans. Here we describe the cases of three children who were referred to the clinical hospital center with the diagnosis of CHD, but with no direct signs of 22q11DS. Investigation of familial data led us to suspect that the mothers could be carriers of 22q11DS. The multiplex ligation-dependent probe amplification (MLPA) testing confirmed that the patients and mothers exhibited 3 Mb 22q11 deletions, which justified the clinical signs in the mothers and the CHD in children. In the presence of a few characteristics that are common of a spectrum of some known syndromes, a familial examination can provide clues to a definitive diagnosis, as well as to the prevention of diseases and genetic counseling of these patients.

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Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)

Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)

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