22q11 Deletion Research Articles

Contemporary Outcomes in Fetuses Diagnosed with Vascular Rings.

Vascular rings are increasingly identified on fetal echocardiography. The purpose of this study is to analyze clinical outcomes and patterns of diagnostic testing in fetuses with vascular rings diagnosed by echocardiography. A retrospective cohort study was performed of fetuses with postnatally confirmed vascular rings from 2017 to 2022. Clinical outcomes included type and timing of symptoms, and timing of surgical intervention. Freedom from symptoms and/or surgery was assessed by Kaplan-Meier analysis. Frequency of genetic and diagnostic testing (barium esophagogram, CT/MRI angiogram, and bronchoscopy) was also assessed. Overall, 46 patients were evaluated (91% with a right aortic arch/left ductus and 4% with a double aortic arch). A vascular ring was isolated in 59%, associated with structural heart lesions in 33%, and associated with noncardiac anomalies in 8%. Prenatal diagnoses increased over time. Symptoms developed in 24% (11/46); 82% (9/11) had respiratory and 45% (5/11) had gastroesophageal complaints. Surgery was performed in 17% (11/46). Symptoms presented bimodally, prior to 100 or after 400days of life. There was no difference in the type of symptoms for early (< 100days) or late (> 400days) presenters. Symptomatic patients received more diagnostic testing. Genetic testing was obtained in 46% and positive in 33%, with 22q11 deletion and Trisomy 21 being identified. Prenatal diagnoses of vascular rings increased over time, with subjects developing symptoms bimodally in early or late infancy. The frequency of genetic testing was suboptimal given the prevalence of genetic abnormalities seen in this population.

Purtscher-like retinopathy in a 19-year-old with maturity-onset diabetes of the young: a case report

BackgroundWe report the first case of Purtscher-like retinopathy in a patient with 17q12 deletion-associated maturity-onset diabetes of the young.Case presentationA 19-year-old diabetic Hispanic male with history of cataracts and toe amputations presented with sudden onset of painless bilateral vision loss for 1 week with no associated trauma. Visual acuity was counting fingers at six feet in both eyes. Dilated retinal examination revealed bilateral peripapillary cotton wool spots and intraretinal hemorrhages, and significant subretinal and intraretinal fluid on optical coherence tomography. Fluorescein angiography revealed arteriolar staining and leakage around the disc with areas of capillary nonperfusion, supporting the diagnosis of Purtscher-like retinopathy. Systemic workup revealed multiple diabetic complications including chronic osteomyelitis of multiple toes, nonhealing diabetic foot ulcers, neurogenic bladder and bowel, and bilateral lower-extremity muscular neuropathies. Genetic evaluation revealed a 17q12 deletion, which is associated with maturity-onset diabetes of the young 5. On follow-up examination, he received a single intravitreal antivascular endothelial growth factor injection in the left eye (off label) for persistent macular edema. Although his retinal edema improved, his visual acuity remained poor.ConclusionsThe presentation of our patient’s multiple diabetic complications along visual symptoms suggests Purtscher-like retinopathy can be a sequela of uncontrolled diabetes. Purtscher-like retinopathy is a rare but possible consideration in diabetic patients who present with acute-onset vision loss.

Genomic landscape of multiple myeloma with extramedullary disease: Results from a large patient database.

8058 Background: Extramedullary disease (EMD) is associated with poor outcomes and the biological mechanisms driving this phenotype are poorly understood. We used the CoMMpass registry data to explore the genomic characteristics of EMD. Methods: The CoMMpass study is a prospective, international registry of newly diagnosed MM. 1143 patients had clinical data. Patients were classified as EMD if they had EMD at any point. Genomic data from bone marrow (BM) samples at diagnosis (whole genome sequencing, whole exome sequencing (WES), and RNA sequencing (RNAseq)) were compared between EMD and non-EMD. A multivariable model was constructed based on univariable results. Differential expression (DEA) and gene set enrichment analysis (GSEA) were performed after normalization using Hallmark and MM transcriptomic subgroups. The top 24 most mutated genes in MM were selected. Results: The median overall survival (mOS) and progression free survival (PFS) was shorter for EMD. The presence of EMD, anemia at diagnosis, age &gt;65 years at diagnosis, ISS stage, and use of ASCT at the first line were independently associated with worse mOS and PFS. EMD was associated with worse mOS (HR 1.7, 95% CI 1.3 - 2.2 p &lt;0.01) and PFS (HR 1.5, 95% CI 1.23 - 1.8, p &lt;0.01) in multivariable analysis and was not abrogated by ASCT, triplet induction or maintenance. Results did not vary when landmark analysis was used. MYC amplification, deletion 18q and 1q amplification were enriched in EMD cases. TP53 mutations and TP53 bi-allelic inactivation (mutation and deletion) were enriched in EMD (Table). DEA identified 1552 genes with increased and 3344 with decreased expression (2.7%, 5.4% of total genes respectively) in EMD when compared to non-EMD. On GSEA, EMD cases were enriched for the CD-1, PR, and CTA myeloma gene expression signatures, in addition to the Hallmark pathways MYC target, E2F targets, G2M checkpoint and unfolded protein response, while the adhesion molecules pathway and MM gene signatures LB, MS, and MF were downregulated in EMD. Conclusions: EMD cases were enriched for TP53 mutations and bi-allelic TP53 inactivation, both of which are prognostic. In addition, MYC amplification, 18q deletion and 1q gain were enriched in EMD which are novel CNA associated with EMD. EMD is also enriched for distinct molecular subgroup, including enrichment for CD-1, PR, and CTA signatures, the latter two are associated with poor outcomes, and the Hallmark pathways MYC, E2F and G2M checkpoints consistent with MYC amplification and PR molecular subgroup. WES and RNAseq of matching BM and EMD tissue samples from our institution is currently being performed. [Table: see text]

Presentation of congenital soft-tissue sarcomas: A single institution experience.

e23551 Background: Pediatric sarcomas make up 10% of pediatric tumors and involve a varied range of histological patterns with different prognosis which creates therapeutic challenges. Neonatal presentation is rare among sarcomas and poses further challenges in therapy. Methods: We present 5 cases of congenital sarcomas reporting pathology, genetics, treatment, and outcomes. We retrospectively identified 5 patients with sarcomas diagnosed in the neonatal period from a single institution in Miami from 2017 – 2022 in order to identify similarities between neonatal sarcomas. Our sarcomas included an embryonal rhabdomyosarcoma (RMS), infantile fibrosarcoma (IFS), rhabdoid tumor, and two undifferentiated sarcomas. Results: The presentation occurred between birth and four days old. Location at presentation was varied. Four of our patients were Nonrhabdomyosarcoma Soft Tissue Sarcomas (NRSTS). Only one patient was diagnosed prenatally, while three were diagnosed at birth, and one at 4 days of life. Three patients presented spindle cell pathology. One of our undifferentiated sarcomas was classified as IFS-like, Archer FusionPlex was negative for mutation. Our other undifferentiated sarcoma showed a COL1A1 gene rearrangement on chromosome 17q.21 with immunostains positive for BCOR, SMARCB1, SMARCA4. Congenital fibrosarcoma showed ETV6 fusion with NTRK and immunostains positive for FLI-1, SMA, CD34, INI-1. The RMS showed focal loss of PTCH1 and FANCC and had immunostains positive for desmin and myogenin. The metastatic rhabdoid tumor showed SMARCB1 whole gene deletion as well as a 570kB deletion in chromosome 22q11.23. Three patients were treated on ARST 0331 with vincristine, doxorubicin, and cyclophosphamide (VAC), with the undifferentiated sarcoma requiring advancement to ARST 0332. The patient with metastatic rhabdoid tumor was treated with AREN 0321. Four patients required surgery. We had 1-year-survival in three patients, all treated on ARST 0331 or ARST 0332. The patient with metastatic rhabdoid tumor died at 4 months of age while on AREN 0321, and our patient with IFS-like sarcoma decompensate and died at ten days old, prior to starting therapy. Conclusions: We show multiple genetic mutations with SMARCB1 alteration in both an undifferentiated sarcoma and a malignant rhabdoid tumor but otherwise found no significant pattern among individual sarcomas. Our cases show good outcomes for patients qualifying for ARST 0331. We highlight the need for improved methods of detection of pediatric tumors in utero.

Cytogenomic Profiling of Chronic Lymphocytic Leukaemia Patients Using DNA Microarray

Introduction: Chronic lymphocytic leukaemia (CLL) is the most frequent adult leukaemia in the Western world. The clinical presentation varies greatly, from very indolent cases to those with aggressive and fast advancing disease. This variation has significant implications for clinical approaches, therapeutic tactics, and, ultimately, survival durations from diagnosis. Acquired chromosomal aberrations play a key role in CLL aetiology. Due to difficulty to obtain abnormal metaphases for analysis, few methods such as fluorescence in-situ hybridization (FISH) and multiplex ligation-dependent probe assay (MLPA) were employed to detect chromosomal aberration however the methods are limited to specific locus only. Thus, this study is aimed to detect the chromosomal aberrations using DNA microarray platform. Methods: In this retrospective study, DNA archive obtained from 7 CLL patients which collected at diagnosis and subjected to Affymetrix CytoScan® 750K single nucleotide polymorphism (SNP) array following the manufacture procedure. The raw data obtained were analysed using the Chromosome Analysis Suite (ChAS) software (Affymetrix) using annotations of genome version GRCh38 (hg38). Result: Out of 7 patients, 4 of them showing deletion of 13q while 3 of them showing deletion of 14q in various region . Some of the deleted loci were too small (0.42-0.6Mb) to be detected by conventional cytogenetic analysis (CCA). There was also the presence of additional chromosomal aberrations that could be missed by CCA, FISH, or MLPA due to cryptic deletion or duplication that was as small as 0.4MB in size. Conclusion: The present study showed that low resolution chromosomal aberration was able to be detected using DNA microarray platform in comparison to CCA, FISH and MLPA.

High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing

BackgroundHigh sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood.MethodsWe employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints.ResultsIn total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes.ConclusionsWe have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.

Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22

This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in SHANK3. It is one of a series of papers written by the European PMS consortium as a consensus guideline. We reviewed the available literature based on pre-set questions to formulate recommendations on counselling, diagnostic work-up and surveillance for tumours related to ring chromosome 22. All recommendations were approved by the consortium, which consists of professionals and patient representatives, using a voting procedure. PMS can only rarely be diagnosed based solely on clinical features and requires confirmation via genetic testing. In most cases, the family will be referred to a clinical geneticist for counselling after the genetic diagnosis has been made. Family members will be investigated and, if indicated, the chance of recurrence discussed with them. Most individuals with PMS have a de novo deletion or a pathogenic variant of SHANK3. The 22q13.3 deletion can be a simple deletion, a ring chromosome 22, or the result of a parental balanced chromosomal anomaly, influencing the risk of recurrence. Individuals with a ring chromosome 22 have an increased risk of NF2-related schwannomatosis (formerly neurofibromatosis type 2) and atypical teratoid rhabdoid tumours, which are associated with the tumour-suppressor genes NF2 and SMARCB1, respectively, and both genes are located on chromosome 22. The prevalence of PMS due to a ring chromosome 22 is estimated to be 10–20%. The risk of developing a tumour in an individual with a ring chromosome 22 can be calculated as 2–4%. However, those individuals who do develop tumours often have multiple. We recommend referring all individuals with PMS and their parents to a clinical geneticist or a comparably experienced medical specialist for genetic counselling, further genetic testing, follow-up and discussion of prenatal diagnostic testing in subsequent pregnancies. We also recommend karyotyping to diagnose or exclude a ring chromosome 22 in individuals with a deletion 22q13.3 detected by molecular tests. If a ring chromosome 22 is found, we recommend discussing personalised follow-up for NF2-related tumours and specifically cerebral imaging between the age of 14 and 16 years.

Parental perspectives on Phelan-McDermid syndrome: Results of a worldwide survey

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder characterised by hypotonia, speech problems, intellectual disability and mental health issues like regression, autism and mood disorders. In the development, implementation and dissemination of a new clinical guideline for a rare genetic disorder like PMS, the parental experienced perspective is essential. As information from literature is scarce and often conflicting the European Phelan-McDermid syndrome guideline consortium created a multi-lingual survey for parents of individuals with PMS to collect their lived experiences with care needs, genotypes, somatic issues, mental health issues and parental stress. In total, we analysed 587 completed surveys from 35 countries worldwide. Based on parental reporting, PMS appeared to be caused by a deletion of chromosome 22q13.3 in 78% (379/486) of individuals and by a variant in the SHANK3 gene in 22% (107/486) of the individuals. Parents reported a wide variety of developmental, neurological, and other clinical issues in individuals with PMS. The most frequently experienced issues were related to speech and communication, learning disabilities/intellectual disability, and behaviour. While most reported issues were present across all age groups and genotypes, the prevalence of epilepsy, lymphoedema, and mental health issues do appear to vary with age. Developmental regression also appeared to begin earlier in this cohort than described in literature. Individuals with PMS due to a 22q13.3 deletion had a higher rate of kidney issues and lymphoedema compared to individuals with SHANK3 variants. Parental stress was high, with specific contributing factors being child and context related in accordance with the PMS phenotype. The survey results led to various validated recommendations in the European PMS guideline including an age specific surveillance scheme, specific genetic counselling, structured healthcare evaluations on sleep and communication and a focus on family well-being.

Consensus recommendations on lymphedema in Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by deletions 22q13.3 or pathogenic variants in the SHANK3 gene. Lymphedema can be a clinical feature in 10–25% of individuals with PMS due to a deletion 22q13.3, but is not observed in those with a SHANK3 variant. This paper forms a part of the European consensus guideline for PMS and focuses on what is known regarding lymphedema in PMS in order to present clinical recommendations.The mechanism causing lymphedema in PMS is unknown. Lymphedema can be suggested by pitting oedema of the extremities or, in later stages, non-pitting swelling. It can occur already at a young age and be progressive if untreated, impacting daily functioning. Lymphedema can be treated using existing general multidisciplinary management guidelines, taking the functioning of the individual with PMS into account. Furthermore, well-known risk factors for the development of lymphedema as lack of physical activities and weight gain/obesity should be addressed. Diagnosis and treatment are best performed in a multidisciplinary centre of expertise.

The Schizophrenia-Associated 3q29 Deletion: Cross-Species Transcriptional Profiling Converges on Mitochondrial Dysregulation

The Schizophrenia-Associated 3q29 Deletion: Cross-Species Transcriptional Profiling Converges on Mitochondrial Dysregulation

Identification of 17q12 microdeletion syndrome in a Latin American patient with maturity-onset diabetes of the young subtype 5: a case report

BackgroundMaturity-onset diabetes of the young comprises a large group of autosomal inherited gene mutations. Maturity-onset diabetes of the young subtype 5 is caused by mutations in the HNF1B gene. This gene is expressed in the early phase of embryonic development in the pancreas, kidneys, liver, and genital tract; therefore, kidney or urinary tract malformations are associated with diabetes mellitus. The 17q12 deletion syndrome is a cause of maturity-onset diabetes of the young subtype 5 that should be considered.Case presentationWe present the case of a 35-year-old Hispanic female patient with a history of bicornuate uterus and polycystic renal disease that required kidney transplant. She had insulin-dependent diabetes, with her mother, maternal grandmother, and great-grandmother showing a similar clinical manifestation. Molecular analysis showed a deletion in chromosome 17q12 involving 15 genes, including HNF1B. Therefore, a diagnosis of deletion syndrome was made.ConclusionsThe 17q12 deletion syndrome represents a rare genetic syndrome that involves different genes, including HNF1B. Principally, it is characterized by the combination of genitourinary tract malformations and diabetes mellitus, similar to our patient.

Atypical meningiomas with an immunohistochemical profile consistent with hypermetabolic or proliferative molecular groups show high mitotic index, chromosomal instability, and higher recurrence risk

The use of adjuvant radiotherapy is controversial for atypical meningiomas undergoing gross total resection. It has recently been proposed that meningiomas may be classified into four molecular groups (MG): immunogenic (MG1), benign NF2-wildtype (MG2), hypermetabolic (MG3), and proliferative (MG4). The two latter have the worst prognosis, and it has been suggested that they can be identified using ACADL and MCM2 immunostainings. We studied 55 primary atypical meningiomas, treated with gross total resection and no adjuvant therapies, to assess whether ACADL and MCM2 immuno-expression may identify patients at higher recurrence risk, thus requiring adjuvant treatments. Twelve cases resulted ACADL-/MCM2-, 9 ACADL + /MCM2-, 17 ACADL + /MCM2 + , and 17 ACADL-/MCM2 + . MCM2 + meningiomas displayed more frequent atypical features (prominent nucleoli, small cells with high nuclear-to-cytoplasmic ratio) and CDKN2A hemizygous deletion (HeDe) (P = 0.011). The immunoexpression of ACADL and/or MCM2 was significantly associated with higher mitotic index, 1p and 18q deletions, increased recurrence rate (P = 0.0006), and shorter recurrence-free survival (RFS) (P = 0.032). At multivariate analysis, carried out including ACADL/MCM2 immuno-expression, mitotic index, and CDKN2A HeDe as covariates, this latter resulted a significant and independent prognosticator of shorter RFS (P = 0.0003).

Auditory and Language Features in Children with 18q Deletion: From Diagnosis to Treatment

Introduction: 18q deletion is a rare genetic condition which occurs approximately 1 in 40,000 live births. Site and size of mutation on DNA may be very different among patients. The aim of this study is to describe three cases of 18q, analyzing their auditory and language skills. A secondary aim is to compare our results with those reported in the literature in order to propose a standardized assessment protocol and guidelines for auditory treatment and rehabilitation. Method: We describe the clinical cases of three pediatric patients with 18q deletion. All children underwent detailed audiological evaluations, including otoscopy, Pure Tone Audiometry (PTA) and Auditory Brainstem Responses (ABRs). We also administered them language and speech tests, depending on children age and skills. We propose different solutions for auditory rehabilitation and we compare our patient’s outcomes with those described in the literature. Results: All children showed hearing and narrow External Auditory Canals (EACs). Type of auditory rehabilitation changed among patients. Comorbidities and severity of the disease varied according to the genetic mutation. Data from the literature review are consistent with our findings. Conclusion: Despite the heterogeneity of phenotypes and severity, hearing loss and stenotic EACs were detected in all our patients with 18q deletion. Accurate diagnosis and follow-up are mandatory to improve auditory and language skills and quality of life. Due to the complexity of the cases, no standardized assessment protocols or treatment could be routinely proposed.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

The Effects of 5 Years of Growth Hormone Treatment on Growth and Body Composition in Patients with Temple Syndrome

Introduction: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal uniparental disomy of chromosome 14, paternal deletion of 14q32.2, or an isolated methylation defect. Most patients with TS14 develop precocious puberty. Some patients with TS14 are treated with growth hormone (GH). However, evidence for the effectiveness of GH treatment in patients with TS14 is limited. Methods: This study describes the effect of GH treatment in 13 children and provides a subgroup analysis of 5 prepubertal children with TS14. We studied height, weight, body composition by dual-energy X-ray absorptiometry, resting energy expenditure (REE), and laboratory parameters during 5 years of GH treatment. Results: In the entire group, mean (95% CI) height SDS increased significantly during 5 years of GH treatment from −1.78 (−2.52; −1.04) to 0.11 (−0.66; 0.87). Fat mass percentage SDS decreased significantly during the first year of GH, and lean body mass (LBM) SDS and LBM index increased significantly during 5 years of treatment. IGF-1 and IGF-BP3 levels rose rapidly during GH treatment, and the IGF-1/IGF-BP3 molar ratio remained relatively low. Thyroid hormone levels, fasting serum glucose, and insulin levels remained normal. In the prepubertal group, median (interquartile range [IQR]) height SDS, LBM SDS, and LBM index also increased. REE was normal at start and did not change during 1 year of treatment. Five patients reached adult height and their median (IQR) height SDS was 0.67 (−1.83; −0.01). Conclusion: GH treatment in patients with TS14 normalizes height SDS and improves body composition. There were no adverse effects or safety concerns during GH treatment.

Computer-aided facial analysis as a tool to identify patients with Silver–Russell syndrome and Prader–Willi syndrome

Genetic syndromes often show facial features that provide clues for the diagnosis. However, memorizing these features is a challenging task for clinicians. In the last years, the app Face2Gene proved to be a helpful support for the diagnosis of genetic diseases by analyzing features detected in one or more facial images of affected individuals. Our aim was to evaluate the performance of the app in patients with Silver–Russell syndrome (SRS) and Prader–Willi syndrome (PWS). We enrolled 23 pediatric patients with clinically or genetically diagnosed SRS and 29 pediatric patients with genetically confirmed PWS. One frontal photo of each patient was acquired. Top 1, top 5, and top 10 sensitivities were analyzed. Correlation with the specific genetic diagnosis was investigated. When available, photos of the same patient at different ages were compared. In the SRS group, Face2Gene showed top 1, top 5, and top 10 sensitivities of 39%, 65%, and 91%, respectively. In 41% of patients with genetically confirmed SRS, SRS was the first syndrome suggested, while in clinically diagnosed patients, SRS was suggested as top 1 in 33% of cases (p = 0.74). Face2Gene performed better in younger patients with SRS: in all patients in whom a photo taken at a younger age than the age of enrollment was available, SRS was suggested as top 1, albeit with variable degree of probability. In the PWS group, the top 1, top 5, and top 10 sensitivities were 76%, 97%, and 100%, respectively. PWS was suggested as top 1 in 83% of patients genetically diagnosed with paternal deletion of chromosome 15q11-13 and in 60% of patients presenting with maternal uniparental disomy of chromosome 15 (p = 0.17). The performance was uniform throughout the investigated age range (1–15 years).Conclusion: In addition to a thorough medical history and detailed clinical examination, the Face2Gene app can be a useful tool to support clinicians in identifying children with a potential diagnosis of SRS or PWS.What is Known:• Several genetic syndromes present typical facial features that may provide clues for the diagnosis.• Memorizing all syndromic facial characteristics is a challenging task for clinicians.What is New:• Face2Gene may represent a useful support for pediatricians for the diagnosis of genetic syndromes.• Face2Gene app can be a useful tool to integrate in the diagnostic path of patients with SRS and PWS.

Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome.

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.

Advances in the field of genetics and difficulties in the diagnosis of di george syndrome.

IntroductionThe spectacular progress of the last decade in the field of genetics is allowing a new development of medicine and the ability to make a better diagnosis. A great example of this is the diagnosis of chromosome 22q11 deletion, which occurs in 1:4000 live births.ObjectivesThis case wants to illustrate the difficulties in the diagnosis, despite technological advances.MethodsExhaustive review of the literatureResultsThis is a 38-year-old male patient diagnosed with chromosome 22q11 deletion in adulthood.Family history of medical problems: mother with genetic diagnosis of chromosome 22q11 deletion, in adulthood, after the diagnosis of her own son.Personal history of medical problems:- Psychiatry: he has been followed up intermittently in psychology since he was 6 years old, due to cognitive difficulties and behavioral alterations. He has had several hospital admissions in psychiatry during adolescence for behavioral disorders and intellectual disability, with possible psychotic symptoms. In treatment with antiepileptics and antipsychotics.- Cardiology: aortic aneurysm and bicuspid aortic valve were detected. The patient underwent surgery in 2018.- Genetics: he is diagnosed with chromosome 22q11 deletion in 2019. This is an inherited mutation of maternal origin that is detected later.- Rheumatology: seropositive rheumatoid arthritis, non-erosive.- Rehabilitation: treatment to improve psychomotor skills, from 6-12 years of age.It is important to emphasize that the diagnosis was made at the age of 35 years, after a more deep study which had been carried out after the debut of the cardiac pathology. In addition, it is very striking that the diagnosis of his mother was made later than the one of the patient himself.Currently, the patient presents serious difficulties in respecting the rules of coexistence at home and in understanding social norms, so that he has not been able to integrate in any environment and remains isolated at home. Serious behavioral alterations with tendency to physical and verbal heteroaggressiveness, difficulty in accepting limits and sexualized and uninhibited behaviors.Clinical judgment: chromosome 22q11 deletion.ConclusionsEarly diagnosis is essential to be able to treat and, above all, prevent the possible complications that this syndrome may present. However, diagnosis is sometimes very complex, despite advances in molecular diagnostic techniques. Therefore, an integrative approach is very valuable, looking at the individual as a whole and not only by systems or medical subspecialties. In addition, it would be very interesting to establish a means of communication between specialties. Finally, it would be a real step forward to integrate all the medical information of each person in a single medical record, an apparently simple aspect, but so far from being possible.Disclosure of InterestNone Declared

Endocrine Abnormalities and Growth Characterization in Colombian Pediatric Patients with 22q11 Deletion Syndrome

Several endocrine manifestations have been described in patients with 22q11 deletion syndrome, including growth retardation, hypoparathyroidism, and thyroid disorders. This study aimed to characterize these abnormalities in a Colombian retrospective cohort of children with this condition. A retrospective study comprising a cohort of children with 22q11 deletion syndrome in Medellín, Colombia followed up between 2011 and 2017 was conducted. Thirty-seven patients with a confirmed diagnosis of 22q11 deletion syndrome were included. 37.8% had some endocrinopathy, the most frequent being hypoparathyroidism (21.6%), followed by hypothyroidism (13.5%), hyperthyroidism (2.7%) and growth hormone deficiency (2.7%). There was wide heterogeneity in the clinical presentation, with late onset of severe hypocalcemia associated with seizure or precipitated in postoperative cardiac surgery, which highlights the importance of continuous follow-up as indicated by the guidelines. Short stature was mainly related to nutritional factors. Growth monitoring is required with the use of syndrome-specific charts and careful monitoring of the growth rate. As previously reported, a significant proportion of patients with endocrine abnormalities were found in this cohort. This highlights that it is essential to carry out an adequate multidisciplinary follow-up, based on the specific clinical guidelines, in order to avoid serious complications such as convulsions due to hypocalcemia. It is important to track size with curves specific to the syndrome and analyze the growth rate.