Search Results (84)

Inherited epidermolysis bullosa (EB) is a heterogeneous clinical entity that includes over 30 phenotypically and/or genotypically distinct inherited disorders, characterized by mechanical skin fragility and bullae formation. Junctional EB (JEB) is an autosomal recessive disease characterized by an intermediated cleavage level within the skin layers, commonly at the “lamina lucida”. Laryngo-onycho-cutaneous syndrome (LOC) is an extremely rare variant of JEB, characterized by granulation tissue formation in specific body sites (skin, larynx, and nails). Although most cases of JEB are caused by pathogenic variants occurring in the genes encoding for classical components of the lamina lucida, such as laminin 332 (LAMA3, LAMB3, LAMC2), integrin α6β4 (ITGA6, ITGB4), and collagen XVII (COL17A1), other variants have also been described. We report the case of a 4-month-old male infant who presented with recurrent bullous and erosive lesions from the first month of life. At the first dermatological evaluation, the patient was agitated and exhibited hoarse breathing, a clinical sign suggestive of laryngeal involvement. Multiple polygonal skin erosions were observed on the cheeks, along with similar isolated, roundish lesions on the scalp and legs. Notably, nail dystrophy and near-complete anonychia were evident on the left first and fifth toes. Due to the coexistence of skin erosions and nail dystrophy in such a young infant, a congenital bullous disorder was suspected, prompting molecular analysis of all potentially involved genes. In the patient’s DNA, clinical exome sequencing (CES) identified a pathogenic variant, apparently in homozygosity, in the exon 1 of the LAMA3 gene (18q11.2; NM_000227.6): c.47G > A;p.Trp16*. The presence of this variant was confirmed, in heterozygosity, in the genomic DNA of the patient’s mother, while it was absent in the father’s DNA. Subsequently, trio-based SNP array analysis was performed, revealing a paternally derived pathogenic microdeletion encompassing the LAMA3 locus (18q11.2). To our knowledge, this is the first reported case of JEB with a LOC-like phenotype caused by a maternally inherited monoallelic nonsense mutation in LAMA3, unmasked by an almost complete deletion of the paternal allele. The combined use of exome sequencing and SNP array is proving essential for elucidating autosomal recessive diseases with a discordant segregation. This is pivotal for providing accurate genetic counseling to parents regarding future pregnancies. Full article

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks’ gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices. Full article

Background/Objectives: Miscarriage is an increasingly common event worldwide arising from various factors, and identifying its etiology is important for planning and managing any future pregnancies. It is estimated that about half of early pregnancy loss cases are caused by genetic abnormalities, while a significantly lower rate is found in late pregnancy loss. Multiplex ligation-dependent probe amplification (MLPA) can detect small changes within a gene with precise breakpoints at the level of a single exon. The aim of our study was to identify the rate of copy number variations (CNVs) in spontaneous pregnancy loss samples after having previously tested them via quantitative fluorescence PCR (QF-PCR), with no abnormal findings. Methods: DNA was extracted from product-of-conception tissue samples, followed by the use of an MLPA kit for the detection of 31 microdeletion/microduplication syndromes (SALSA^® MLPA^® Probemix P245 Microdeletion Syndromes-1A, MRC-Holland, Amsterdam, The Netherlands). Results: A total of 11 (13.1%) out of the 84 successfully tested samples showed CNVs. Duplications accounted for 9.5% of the analyzed samples (eight cases), while heterozygous or hemizygous deletions were present in three cases (3.6%). Among all the detected CNVs, only three were certainly pathogenic (3.6%), with two deletions associated with DiGeorge-2 syndrome and Rett syndrome, respectively, and a 2q23.1 microduplication syndrome, all detected in early pregnancy loss samples. For the remaining cases, additional genetic tests (e.g., aCGH/SNP microarray) are required to establish CNV size and gene content and therefore their pathogenicity. Conclusions: MLPA assays seem to have limited value in detecting supplementary chromosomal abnormalities in miscarriages. Full article

Background/Objectives: Prader–Willi Syndrome (PWS) is a neurodevelopmental disease associated with multiple behavioral features, including a prevalence for psychosis. The genetic causes of PWS are well characterized and involve the silencing or deletion of the paternal copy of a region of chromosome 15q11–13. One gene within this region, Snord116, a non-coding RNA, has been determined to have a determinant role in the manifestation of PWS. However, it remains unclear as to how the deletion of this allele can affect activity in the brain and influence psychosis-like behaviors. Methods: In this study, we assessed the effects of the microdeletion of the paternal copy of Snord116 on regional neural activity in psychosis-associated brain regions and psychosis-like behaviors in mice. Results: The results suggest that Snord116 deletion causes increased c-Fos expression in the hippocampus and anterior cingulate cortex. Snord116 deletion also results in behavioral phenotypes consistent with psychosis, most notably in stressful paradigms, with deficits in sensorimotor gating and augmented contextual as well as cued fear conditioning. Conclusions: These results implicate the targets of Snord116 in the presentation of a psychosis-like state with regional specificity. Full article

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes. Full article

This study investigated the genetic causes of atypical cerebral palsy (CP) through chromosomal microarray (CMA) and exome sequencing (ES) in a cohort of 10 Korean patients to identify variants and expand the spectrum of mutations associated with atypical cerebral palsy. Whole ES and/or genome sequencing (GS) after routine karyotyping and CMA was performed to identify causative variants and expand the spectrum of mutations associated with atypical CP. In cases of atypical CP, scoliosis and/or kyphosis, ranging from mild to severe, were present in all patients. Epilepsy was a comorbidity in seven patients (70%), and intellectual disability (ID) was observed in varying degrees. This study identified three copy number variations (CNVs), including 15q11.2 microdeletion (n = 1), 17p11.2 duplication (n = 1), and 12p13.33p11.23 duplication/18p11.32 microdeletion (n = 1), and six likely pathogenic variants (LPVs) or pathogenic variants (PVs) detected in the SLC2A1, PLAA, CDC42BPB, CACNA1D, ALG12, and SACS genes (n = 6). These findings emphasize the significance of incorporating genetic testing into the diagnostic process for atypical CP to improve our understanding of its molecular basis and inform personalized treatment strategies. To further advance this research, future studies should focus on exploring genotype–phenotype correlations, assessing the functional impact of identified variants, and increasing the sample size to validate the observed patterns. Full article

Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development. Clinical report: Here, we report three individuals who present with clinical features of KBG syndrome. These individuals carry microdeletions encompassing only the non-coding exon 1 of ANKRD11 and its upstream region. Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients. Conclusions: We concluded that microdeletions involving non-coding exon 1 of ANKRD11 lead to KBG syndrome. Our study suggests the utility of transcriptome analysis in aiding the interpretation of novel copy number variants in the non-coding genomic region of ANKRD11. Full article

Background/Objectives: 22q11.2 microdeletion syndrome (22q11DS) is a genetic disease caused by aberration of chromosome 22 that results in some phenotypic features and developmental disorders. This paper presents a cross-sectional study on speech and communication of Polish children with 22q11DS. Methods: Individuals affected with 22q11DS may show difficulties in functioning, including speech and hearing. Therefore, we prepared a speech development questionnaire and employed it to obtain data from parents (or legal guardians) of 54 children with 22q11DS. The questionnaire covered the following speech and communication development stages: babbling, using first words, first sentences, verbal and non-verbal communication, speech disfluencies, hearing loss, speech intelligibility, difficulties in interpersonal contact, and participation in speech therapy. The obtained answers underwent statistical analysis to verify relationships between the stages of personal development and selected dysfunctions and disorders. Results: In the study group we observed delays in achieving subsequent speech developmental stages and that hearing loss was associated with delays in producing first words. Hearing loss was reported in about a quarter of cases, but a significant proportion of children (55.56%) reported speech disfluencies, which had not been emphasized in previous works, where hearing loss is considered a common co-occurring disorder. Conclusions: Our findings suggest that this may represent a phenomenon associated with 22q11DS that warrants further investigation using standardized tests for assessing disfluencies. Additionally, we observed that speech therapists and caregivers were perceived as not fully aware of the speech development impairments caused by 22q11DS. These preliminary observations point to the need for future studies and increased awareness efforts in this area. Full article

Background: Balanced chromosomal translocations occur in approximately 0.16 to 0.20% of live births. While most carriers are phenotypically normal, they are at risk of generating unbalanced gametes during meiosis, leading to genetic anomalies such as aneuploidies, deletions, duplications, and gene disruptions. These anomalies can result in spontaneous abortions or congenital anomalies, including neurodevelopmental disorders. Complex chromosomal rearrangements (CCRs) involving more than two chromosomes are rare but further increase the probability of producing unbalanced gametes. Neurodevelopmental disorders such as Angelman syndrome (AS) and duplication 15q11q13 syndrome (Dup15q) are associated with such chromosomal abnormalities. Methods: This study describes a family with a de novo maternal balanced double translocation involving chromosomes 13, 19, and 15, resulting in two offspring with unbalanced chromosomal abnormalities. Cytogenetic evaluations were performed using GTG banding, fluorescence in situ hybridization (FISH), and low-pass whole-genome sequencing (LP-WGS). Methylation analysis was conducted using methylation-sensitive high-resolution melting (MS-HRM) to diagnose Angelman syndrome. Results: The cytogenetic and molecular analyses identified an 8.9 Mb duplication in 15q11.2q13.3 in one child, and an 8.9 Mb deletion in the same region in the second child. Both abnormalities affected critical neurodevelopmental genes, such as SNRPN. FISH and MS-HRM confirmed the chromosomal imbalances and the diagnosis of Angelman syndrome in the second child. The maternal balanced translocation was found to be cryptic, contributing to the complex inheritance pattern. Conclusion: This case highlights the importance of using multiple genetic platforms to uncover complex chromosomal rearrangements and their impact on neurodevelopmental disorders. The findings underscore the need for thorough genetic counseling, especially in families with such rare chromosomal alterations, to manage reproductive outcomes and neurodevelopmental risks. Full article

Background/Objectives: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods: We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results: CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations (p = 0.019). Conclusions: The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling. Full article

Background/Objectives: Truncus arteriosus communis (TAC) is a rare congenital heart defect characterized by a single arterial trunk that supplies systemic, pulmonary, and coronary circulations. This defect, constituting approximately 1–4% of congenital heart diseases, poses significant challenges in prenatal diagnosis, management, and postnatal outcomes. Methods: A retrospective analysis was conducted at the local tertiary referral center on cases of TAC diagnosed prenatally between 2019 and 2024. Additionally, a systematic literature review was performed to evaluate the accuracy of prenatal diagnostics and the presence of associated anomalies in fetuses with TAC and compare already published data with the local results. The review included studies that especially described the use of fetal echocardiography, the course and outcome of affected pregnancies, and subsequent management strategies. Results: The analysis of local prenatal diagnoses revealed 14 cases. Of the 11 neonates who survived to birth, the TAC diagnosis was confirmed in 7 instances. With all seven neonates undergoing surgery, the intention-to-treat survival rate was 86%, and the overall survival rate was 55%. By reviewing published case series, a total of 823 TAC cases were included in the analysis, of which 576 were diagnosed prenatally and 247 postnatally. The presence of associated cardiac and extracardiac manifestations as well as genetic anomalies was common, with a 22q11 microdeletion identified in 27% of tested cases. Conclusions: Advances in prenatal imaging and early diagnosis have enhanced the management of TAC, allowing for the detailed planning of delivery and immediate postnatal care in specialized centers. The frequent association with genetic syndromes underscores the importance of genetic counseling in managing TAC. An early surgical intervention remains crucial for improving long-term outcomes, although the condition is still associated with significant risks. Long-term follow-up studies are essential to monitor potential complications and guide future management strategies. Overall, a coordinated multidisciplinary approach from prenatal diagnosis to postnatal care is essential for improving outcomes for individuals with TAC. Full article

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care. Full article

The relatively rare proximal 17q12 microdeletion, including the deletion of the HNF1B gene, is associated with renal cysts and diabetes syndrome (RCAD). This genomic rearrangement results in a wide range of phenotypes, including renal cysts and diabetes, which are consistent with maturity-onset diabetes of the young type 5 (MODY5), Mullerian aplasia/dysgenesis, autism spectrum disorder and schizophrenia, speech delay, learning difficulties, transient neonatal hypercalcemia, and neonatal cholestasis. We describe a girl with a 17q12 microdeletion identified using CGH array analysis (about 1.4 Mb, including HNF1B and LHX1 genes). The same deletion was identified in her mother. The proband had shown cystic and hypodysplastic bilateral kidneys since birth and hypertension, while her mother had bilateral renal cysts and diabetes. Despite suggestive findings in the girl and in the mother, no clinical suspicion arose, and genetic testing was carried out only after referral to a pediatric nephrologist. In children, the identification of 17q12 microdeletion may have a significant impact on the diagnosis, prognosis, and management of renal disease and early-onset type II diabetes. This family with a 17q12 microdeletion confirms intrafamilial phenotypic variability and highlights the importance of including it early on in the analysis of the diagnostic workup of children with renal cystic diseases. Full article

Congenital heart disease (CHD) is the most commonly detected congenital anomaly and affects up to 1% of all live-born neonates. Current guidelines support the use of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) as diagnostic approaches to identify genetic causes. The aim of our study was to evaluate the diagnostic yield of CMA and NGS in a cohort of neonates with both isolated and syndromic CHD. The present study included 188 infants under 28 days of age with abnormal echocardiography findings hospitalized at the Department of Neonatology, UMC Ljubljana, between January 2014 and December 2023. Phenotypic data were obtained for each infant via retrospective medical chart review. We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of neonates. The most frequent genetic diagnoses in diagnosed cases were 22q11.2 microdeletion and CHARGE syndromes, followed by Noonan syndrome and Williams syndrome. In addition, we detected variants of uncertain significance in 4.8% (9/188) of neonates. Timely genetic diagnosis is important for the detection of syndrome-related comorbidities, prognosis, reproductive genetic risks and, when appropriate, genetic testing of other family members. Full article

The 22q11.2 region is highly susceptible to genomic rearrangements leading to multiple genomic disorders, including 22q11.2 microdeletion syndrome (22q11.2 DS) (MIM# 188400), 22q11.2 microduplication syndrome (MIM# 608363), supernumerary der(22)t(11;22) syndrome (also known as Emanuel Syndrome; MIM# 609029), and Cat Eye Syndrome (MIM# 115470). In this study, we present data on causes of mortality, average age of death, and the existing associated risk factors in patients with 22q11.2 rearrangements. Our cohort included 223 patients (120 males and 103 females) with confirmed diagnoses of 22q11.2 rearrangements diagnosed through molecular techniques (FISH, MLPA, and CMA). Relatives from patients who have been molecularly confirmed with 22q11.2 rearrangements have also been added to the study, regardless of the presence or absence of symptoms. Of these 223 individuals, 21 (9.4%) died. Deceased patients’ rearrangements include 19 microdeletions, 1 microduplication, and 1 patient with a marker chromosome. The median age of death was 3 months and 18 days (ranging from 3 days to 34 years). There were 17 patients who died at pediatric age (80.95%), 3 died at adult age (14.28%), and for 1 of whom, the age of death is unknown (4.76%). Eighteen patients were White Mediterranean (European non-Finnish) (85.71%) whereas three were Amerindian (South American) (14.28%). Mortality from cardiac causes accounted for 71.42%. The second most frequent cause of death was sepsis in two patients (9.52%). One patient died from respiratory failure (4.76%) and one from renal failure (4.76%). Information regarding the cause of death was not available in two patients (9.52%). Most patients who died were diagnosed within the first week of life, the majority on the first day. This study adds additional information on mortality in one of the largest cohorts of patients with 22q11.2 rearrangements in more than 30 years of follow-up. Full article