Speech and language abilities of children with the familial form of 22q11.2 deletion syndrome

The 22q11.2 Deletion Syndrome (22q11.2DS), which encompasses Shprintzen syndrome, DiGeorge and velocardiofacial syndrome, is the most common microdeletion syndrome in humans with an estimated incidence of approximately 1/4000 per live births. After Down syndrome, it is the second most common genetic syndrome associated with congenital heart malformations. The mode of inheritance of the 22q11.2DS is autosomal dominant. In approximately 72-94% of the cases the deletion has occurred de novo, while in 6 to 28% of patients deletion was inherited from a parent. As a part of a multidisciplinary study we examined the speech and language abilities of members of two families with inherited form of 22q11.2DS. The presence of 22q11.2 microdeletion was revealed by fluorescence in situ hybridization (FISH) and/or multiplex ligation-dependent probe amplification (MLPA). In one family we detected 1.5 Mb 22q11.2 microdeletion, while in the other family we found 3Mb microdeletion. Patients from both families showed delays in cognitive, socio-emotional, speech and language development. Furthermore, we found considerable variability in the phenotypic characteristics of 22q11.2DS and the degree of speech-language pathology not only between different families with 22q11.2 deletion, but also among members of the same family. In addition, we detected no correlation between the phenotype and the size of 22q11.2 microdeletion

EP12.075 Detection rate of 22q11.2 microdeletion using strict diagnostic criteria

Background/Objectives: 22q11.2 microdeletion, detected in patients with 22q11.2 Deletion Syndrome (22q11.2DS), is the most common microdeletion syndrome in humans. 22q11.2DS has high risk for neurodevelopmental disorders and is associated with more than 180 malformations. Many investigations of the 22q11.2 microdeletion applying different recruitment criteria, revealed detection rate ranging from zero to 34.7%. Here we analyzed the frequency of 22q11.2 microdeletion among children having at least two out of five major characteristics of 22q11.2DS: congenital heart malformations (CHM), facial dysmorphism, immunological problems, palatal clefts and hypocalcemia. Methods: Children with clinical characteristics of 22q11.2DS were analyzed. Fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analysis were applied for detection of 22q11.2 microdeletion. Results: 22q11.2 microdeletion was detected in approximately 40% of children. CHM was found in all patients with 22q11.2 microdeletion. Dysmorphic facial features were present in about 45%, immunological problems in 30%, overt cleft palate in about 4% and hypocalcemia in approximately 60% of patients with 22q11.2 microdeletion. Conclusion: When at least two major features of 22q11.2DS are taking into consideration higher detection rate is obtained compared to one-feature criterion. These criteria could be considered by centers in low-income countries.Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: e-Poster

Speech Sounds Production, Narrative Skills, and Verbal Memory of Children with 22q11.2 Microdeletion

22q11.2 deletion syndrome (22q11.2DS), the most frequent microdeletion syndrome in humans, is related to a high risk of developing neurodevelopmental disorders. About 95% of patients with 22q11.2DS have speech and language impairments. Global articulation, story generation, and verbal memory tests were applied to compare articulatory characteristics of speech sounds, spontaneous language abilities, and immediate verbal memory between four groups of Serbian-speaking children: patients with 22q11.2DS, children with clinical presentation of 22q11.2DS that do not have the microdeletion, children with non-syndromic congenital heart defects, and their peers with typical speech–sound development. The obtained results showed that children with this microdeletion have impaired articulation skills and expressive language abilities. However, we did not observe weaker receptive language skills and immediate verbal memory compared to healthy controls. Children with 22q11.2DS should be considered a risk category for the development of speech–sound pathology and expressive language abilities. Since speech intelligibility is an instrument of cognition and adequate peer socialization, and language impairment in school-aged children with 22q11DS might be an indicator of increased risk for later psychotic symptoms, patients with 22q11.2 microdeletion should be included in a program of early stimulation of speech–language development immediately after diagnosis is established

Genomic and clinical findings in patients with 22q11.2 duplication syndrome

Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD), schizophrenia, and intellectual disability, are caused by disruption of early brain development. NDDs represent important public health challenge in modern societies with prevalence of about 10 to 15% of all births and the tendency of increasing worldwide. On the other side, treatments of NDDs are focused on symptoms due to limited understanding of underlying pathophysiological mechanisms. Individuals with the 22q11.2 duplication syndrome (22q11.2dup), caused by heterozygous 22q11.2 microduplication, have an elevated risk of developing NDDs. Literature data revealed that ASD is detected in 14-25% of patients with 22q11.2dup while schizophrenia is less common in these patients than in the general population, suggesting that 22q11.2dup might be protective against schizophrenia. We investigated genomic and clinical findings in cohort of 8 patients with 22q11.2dup. The majority of patients have 3Mb duplication. Five patients have 22q11.2 microduplication inherited from their parents. Other CNVs or SNVs are detected in 5 out of 8 patients. Common medical anomalies in our cohort of patients include developmental delay, facial dysmorphism, heart malformations, anomalies of the skeletal system, and anomalies affecting the eye. Characterization of a cohort of patients with 22q11.2dup is important since 22q11.2dup represents a powerful model to get insights into the molecular mechanisms underlying NDDs.BOOK OF ABSTRACTS: 8th CONGRESS OF SERBIAN NEUROSCIENCE SOCIETY with international participation 31 May – 2 June 2023. Belgrade, Serbi

EP06.016 22q11.2 microdeletion is the most common genomic abnormality in Serbian newborns with critical congenital heart disease and could be rapidly detected by Multiplex ligation probe amplification analysis

Background/Objectives: Genetic tests may facilitate rapid and effective diagnostics but unfortunately their high costs usually limit their application in all patients (1). We aimed to investigate the utility of rapid, cost effective and high sensitive Multiplex ligation probe amplification analysis (MLPA) for detection copy number variants (CNV) in newborns with critical CHD, admitted to the Neonatal Intensive Care Unit (NICU). Methods: Study included 100 consecutive newborns admitted to the NICU, University Children’s Hospital in Belgrade from August 2014 to September 2019. Patients with viable trisomies (21, 18 and 13) were excluded. All participants were tested by MLPA analysis using SALSA MLPA P250-B2 Di George and SALSA MLPA P311-B1 Congenital Heart Disease probemixes (MRC Holland, The Netherland). Results: Pathogenic CNVs were identified in ten (10%) patients. Nine of them had 22q11.2 deletion detected by both kits while one patient had 3p25 deletion detected by P311 kit. Conclusion: Genetic evaluation of all newborns with critical CHD admitted to the NICU by rapid and inexpensive MLPA analysis using combination P250 and P311 SALSA probemixes could contribute to high detection rate of pathogenic variants.Abstracts from the 55th European Society of Human Genetics (ESHG) Conferenc

Potentially relevant variants of unknown significance in NGS-tested patients with suspected skeletal dysplasia

ACMG recognizes five different categories of sequence variants identified by next generation sequencing (pathogenic, likely pathogenic, variants of unknown significance, likely benign and benign). Sometimes, potentially relevant gene variants could be categorized as variants of unknown significance according to the level of available evidences. Because of that, detailed assessment of the phenotype-genotype correlation by the clinical geneticist in each individual case is crucially important. The interpretation and classification of a variant may change over time. Variant reinterpretation is defined as the practice of reevaluating all the evidence available about the pathogenicity of a genetic variant and taking into account any new evidence that is made available since the previous interpretation. For the last seven years, we had 168 patients with clinically suspected locus heterogeneous skeletal dysplasia. Next generation sequencing (NGS) using clinical exome sequencing or whole exome sequencing was performed for all. All patients underwent detailed phenotype-genotype correlation investigation. Molecular diagnosis by determining the pathogenic or likely pathogenic causative gene variant(s) was established for 102 out of 168 patients (60.71%). Additionally, in 10 patients (5.95%) variant of unknown significance (VUS) with good phenotype-genotype correlation was identified. These VUS variants could be potentially, and possibly are, causal, although there are no reliable evidences of their pathogenicity at the moment. In one of the positive patients in our study, the variant was initially classified as VUS, but with new evidence it was reclassified as likely pathogenic. In the present study, a potentially relevant variant of unknown significance was detected in 5.95% of patients, which is a non-negligible proportion. For all these patients, we have organized clinical follow-up with periodic reinterpretation and reclassification of the detected variants.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Application of principal component analysis (PCA) and analytical hierarchy process (AHP) in analysis of articulatory characteristics of phonemes of children with 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS is caused by 22q11.2 microdeletion, one of the strongest known risk factors for development of neurodevelopmental disorders. About 70% patients with 22q11.2DS have speech and language impairments. In the literature, there is no data about articulatory characteristics of phonemes of children with 22q11.2DS, monolingual native speakers of South Slavic languages. Here we, by applying Global Articulation Test, analyzed articulatory characteristics of phonemes of children with 22q11.2DS, monolingual native speakers of the Serbian language (group E1), children with a phenotype resembling 22q11.2DS but without the microdeletion (group E2), children with non-syndromic congenital heart malformations (since children with these malformations may exhibit a speech and language impairments) (group E3) and their peers with typical speech-sound development (group C). Results of PCA indicated that the groups can be distinguished based on the pronunciation of phonemes, and that the pronunciation of the phonemes “Č ⟨tʃ⟩”, “Dž ⟨ʤ⟩”, “Š ⟨∫⟩”, “Ž ⟨ʒ⟩”, “R”, and “Lj ⟨ʎ⟩” contributes the most to the variability between the groups. Results of AHP revealed that the pronunciation of the phonemes “Č ⟨tʃ⟩”, “Dž ⟨ʤ⟩”, “Š ⟨∫⟩”, “Ž ⟨ʒ⟩”, “R”, and “Lj ⟨ʎ⟩” was rated the worst in the group E1. In conclusion, obtained results indicate that the presence of 22q11.2 microdeletion influences articulation skills of carriers.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

Copy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4-BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers' cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.info:eu-repo/semantics/publishedVersio

Mowat-Wilson syndrome : growth charts

Background Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of theZEB2gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. Results In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.Peer reviewe