Molecular Syndromology最新文献

Introduction: Current guidelines recommend broad sequencing as a first-tier test for epilepsy, identifying a genetic etiology in 40% of cases. Sequencing subsequently increases the number of patients identified with variants of uncertain significance (VUSs). Clinicians desire additional investigatory methods to better classify these VUSs.

Case presentation: The HNRNPU gene (MIM #602869) is associated with a neurodevelopmental condition characterized by intellectual disability and developmental delay, epilepsy, and characteristic facial features. To date, only de novo variants with complete penetrance have been described. We present a 7-year-old female with HNRNPU variant c.669_691dup; p.Gly231Valfs*116, classified as both pathogenic (Laboratory A) and as a VUS (Laboratory B). This patient exhibits an isolated seizure phenotype, and familial studies revealed the proband's father (asymptomatic), paternal uncle (epilepsy), and paternal grandmother (asymptomatic) all carry this variant. Laboratory B theorized the potential for alternative splicing, reducing concerns about pathogenicity. Methylation studies were pursued for more accurate classification and are conclusively negative for the HNRNPU episignature. This, in the context of the variant not segregating with the familial epilepsy phenotype, indicates a benign classification for the c.669_691dup; p.Gly231Valfs*116 variant.

Conclusion: The number of epilepsy patients with nondiagnostic genetic results requires additional modes of investigation. Reclassification often takes years due to the novelty of variants identified. This case highlights the importance of laboratory scrutiny when multiple variants are detected, the need for greater data sharing between laboratories to reduce inconsistent classifications, and the utility of ancillary testing, such as methylation studies, to aid in VUS reclassification.

Introduction: Neonatal severe hyperparathyroidism (NSHPT) is a rare but life-threatening disorder caused by inactivating variants in the calcium-sensing receptor (CASR), resulting in severe hypercalcemia during the neonatal period. Infants with NSHPT may present with severe hypercalcemia, hyperparathyroidism, growth retardation, and respiratory distress. If untreated, NSHPT can lead to life-threatening complications. Due to its rarity, few cases have been reported in the literature.

Case presentation: A 4-day-old girl presented with jaundice, weight loss, and hypercalcemia (16 mg/dL). On physical examination, she appeared dehydrated and hypotonic, and had facial dysmorphisms. Laboratory results revealed markedly elevated parathyroid hormone levels (1,769 pg/mL) and low urinary calcium excretion. Despite initial treatment with hydration and furosemide, her hypercalcemia persisted. Cinacalcet was started but failed to control calcium levels, leading to the need for a subtotal parathyroidectomy at 2.5 months of age. Genetic testing identified a homozygous mutation in the CASR gene (p.Met741LeufsTer24). Postoperatively, the patient developed hypocalcemia due to hungry bone syndrome and later experienced recurrent hypercalcemia, which was managed with pamidronate followed by calcitriol. At 21 months of age, she remains normocalcemic on daily calcitriol.

Conclusion: This case highlights the challenges in managing NSHPT, especially in cases resistant to medical treatment. Subtotal parathyroidectomy proved essential for controlling hypercalcemia. Continued documentation of NSHPT cases will help improve treatment strategies and outcomes for this rare condition.

Introduction: This is a preliminary study to investigate a feasible genotype-phenotype correlation by defining ophthalmological findings in different genotypes of Down syndrome (DS).

Methods: The study included 62 eyes of 31 DS patients. Patients were further subgrouped according to cytogenetic forms of DS. A comprehensive ophthalmological examination was performed and, biometric, keratometric, and pachymetric parameters were evaluated.

Results: The mean best-corrected visual acuity (BCVA) of trisomy 21 was 0.41 ± 0.14 (0.1-0.6) and was 0.6 ± 0.09 (0.5-0.7) for both mosaic and translocation trisomy 21 (p = 0.004). While 6 of the trisomy 21 patients (24%), 2 of the mosaic patients (66.7%), and all of the three translocation type patients had a normal accommodation response, the remaining patients had accommodation lags (p = 0.013).

Conclusions: Lens opacities and fundus abnormalities were more common in trisomy 21 (p < 0.001). The angle kappa was larger in trisomy 21 and smallest in the translocation trisomy 21 (p = 0.014). K₂ and corneal apex curvature were highest in trisomy 21 (p = 0.05 and p = 0.006, respectively). BCVA and accommodation response were reduced whereas lenticular opacities and fundus abnormalities were more common in trisomy 21. In addition, central cornea was steeper and angle kappa was larger. Further studies with larger cohorts would display differences among subgroups of cytogenetic abnormality.

Introduction: Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. The most common forms include classic types I, II, III, and IV, according to the classification of Sillence, caused by variants in the COL1A1 or COL1A2 genes. This report describes a case series of patients with OI type I confirmed by whole genome sequencing, highlighting the clinical and radiological manifestations of one atypical family.

Case presentation: Six individuals (1M:5F), aged 8 months to 34 years at their first consultation, were enrolled. All were clinically classified as OI type I due to the presence of osteopenia associated with blue sclerae and bone fractures; four presented with short stature, two with hearing loss, and one with fragile teeth; molecular testing confirmed that all presented with heterozygous pathogenic or likely pathogenic variants in the COL1A1 gene. In one family, an unusual presentation was observed in the patient and her daughter, both of whom presented with severe short stature (Z-score <-6), abnormal skull shape (bathrocephaly), codfish vertebrae, bowing of the long bones in the lower limbs, and serpentine fibulas.

Conclusion: Bathrocephaly and serpentine fibula are rarely reported in classical OI types and are more frequently associated with other skeletal dysplasias, such as Hajdu-Cheney syndrome. This case report highlights the importance of recognizing underrated manifestations in OI and underscores the need for molecular confirmation.

Introduction: ATP1A3-related disorders encompass a clinically heterogeneous spectrum that includes previously defined dominantly inherited phenotypes such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, as well as more complex and overlapping presentations.

Case presentation: In this study, we present 2 pediatric cases that expand the phenotypic and genotypic spectrum of ATP1A3-associated disease. Both patients presented with "Guillain-Barré syndrome (GBS)-like episodes" characterized by acute-onset encephalopathy, ataxia, areflexia, and sensorimotor deterioration following febrile infections. Prominent paroxysmal postural abnormalities and dystonia were noted in both cases; however, the overall clinical features blurred the classical boundaries between CAPOS and other ATP1A3-associated phenotypes. The first patient carried the previously reported heterozygous ATP1A3(NM_001256214.2):c.2491G>A(p.Glu831Lys) variant, classically associated with CAPOS, and also exhibited sensorineural hearing loss with a positive family history. The second patient harbored a novel ATP1A3(NM_152296.5):c.2266C>T p.(Arg756Cys)(Clinvar: VCV000425189.38) variant and displayed oculomotor apraxia and chorea during episodes.

Conclusion: These cases underscore the importance of considering ATP1A3 variants in children presenting with GBS-like features, infection-triggered neurological attacks, and mixed movement disorders. Our findings highlight the diagnostic value of genetic testing in atypical neuroregression syndromes and contribute to the recognition of "blended" ATP1A3 phenotypes beyond classical diagnostic entities. The novel pathogenic variant further supports ongoing efforts to refine genotype-phenotype correlations within this evolving group of neurological disorders.

Objective: Somatic mosaic activating PIK3CA variants are a well-established cause of segmental overgrowth phenotypes, whereas germline PIK3CA variants are rare and clinically heterogeneous. We report 2 unrelated patients - 1 with a somatic mosaic and 1 with a de novo germline PIK3CA variant - with longitudinal clinical follow-up.

Case presentation: Patient 1 carried NM_006218.4:c.1412C>T; p.(Pro471Leu) in the C2 domain and presented with macrocephaly, generalized overgrowth, epilepsy, and structural brain anomalies; mosaicism was supported by an attenuated mutant signal on Sanger sequencing. Patient 2 harbored a de novo NM_006218.4:c.323G>A; p.(Arg108His) in the N-terminal p85-binding region and showed macrocephaly, attention-deficit/hyperactivity disorder, and mitral annular disjunction/mitral valve prolapse with aortic root dilatation.

Conclusion: These 2 cases illustrate PIK3CA-related phenotypes arising from somatic mosaic and germline contexts and document their clinical course over time. Larger, well-characterized cohorts and complementary functional assays are needed to refine genotype-phenotype relationships, inform clinical care, and evaluate targeted therapies.

Introduction: Infantile-onset Pompe disease (IOPD), which presents with a broad spectrum of nonspecific findings in newborns and lacks a clearly defined clinical picture, is a significant factor that delays patients' access to diagnosis and treatment. In this disease, insufficient diagnosis rates, low levels of clinical suspicion, and delays in diagnosis are the main problems that hinder early and accurate diagnosis. This study aims to address diagnostic and therapeutic challenges by elucidating the functional roles and associations of microRNAs (miRNAs) in the pathogenesis of IOPD. As a result of comparative data analysis, an inventory of known and novel miRNA sequences predicted to target pathogenic pathways associated with IOPD was established.

Methods: In this study, IOPD and control samples from GSE38680 data were normalized on the Affymetrix platform. Differential gene expression analysis was performed using the limma package, and common differentially expressed (DEGs) were identified. Subsequently, significant signaling pathways were identified using WebGestalt and Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases, and the false discovery rate (FDR) correction was applied. Finally, miRNA expression analysis and miRNA interactions associated with IOPD genes were examined using R packages such as miRNATap and multiMiR.

Results: In this study, 1,967 DEGs (1,108 upregulated, 859 downregulated) were identified in the GSE38680 data. GO and KEGG analyses revealed biological processes associated with IOPD, particularly muscle function and the lysosome pathway. In the analysis of miRNAs associated with the DEGs, 10 miRNAs were predicted to bind directly to the 3'-untranslated region (UTR) of the GAA gene.

Conclusion: Early diagnosis is critical to prevent or mitigate irreversible organ damage associated with the progression of IOPD, and circulating miRNAs may serve as additional biomarkers for diagnosis, disease severity, and treatment response. This study used high-throughput technology to identify potential miRNAs for IOPD.

Introduction: Partial duplications involving chromosome 2p are rare genomic events associated with variable phenotypic outcomes, ranging from craniofacial abnormalities, organ malformations to developmental delays. Prenatal identification of such duplications has become increasingly common with advances in chromosomal microarray technology, but predicting postnatal manifestations remains challenging. This report presents a de novo 32 Mb duplication of 2p21p24.3, detected prenatally, in a male patient who demonstrated unique clinical features and multisystem involvement postnatally.

Case presentation: A 29-year-old pregnant female was referred for genetic evaluation following prenatal detection of flat nasal bridge, frontal bossing, short extremities, micropenis, and suspected hypospadias. Chromosomal microarray analysis revealed a 32 Mb duplication of 2p21p24.3, confirmed as de novo by parental testing. Postnatally novel features such as subglottic haemangioma, preauricular pit, and behavioural symptoms related to facial contact were noted. Growth delay, craniofacial dysmorphism, congenital heart defects, and genital anomalies were also observed. A multidisciplinary approach involving clinical genetics was critical for addressing the patient's complex medical needs. Despite ongoing supportive care, the patient continues facing significant developmental and medical challenges, underscoring the need for long-term follow-up as well as genotype-phenotype correlations.

Conclusion: This case broadens the clinical spectrum of partial trisomy 2p by documenting unique features, including subglottic haemangioma, behavioural symptoms, and preauricular pit. It highlights the value of integrating prenatal diagnostics with detailed postnatal phenotypic assessment to improve understanding of genotype-phenotype correlations in rare chromosomal duplications. Although the PPP1CB gene within the region is considered a plausible candidate for explaining some of the patient's cardinal features, dysmorphism (prominent forehead, preauricular ear pits, low-set, posteriorly rotated ears), cardiac-neurological problems, other genes associated with defined syndromes - whose clinical manifestations overlap to varying degrees - were also considered as potential contributors to the clinical picture, such as MYCN, DNMT3A, DPYSL5, and SOS1. These insights can aid clinicians in genetic counselling, anticipatory guidance, and management of similar cases in the future.

Introduction: RASopathies are among the most prevalent genetic syndromes caused by variants in the Ras/MAPK signaling pathway, affecting various systems such as the heart, craniofacial features, skin, musculoskeletal system, hearing, and vision. They can also increase the risk of secondary malignancies. Despite clinical overlaps, distinguishing features are crucial for diagnosis, as different variants lead to distinct clinical implications. This study reviews the molecular and clinical characteristics of RASopathies, focusing on neurofibromatosis type 1 (NF1) and non-NF1 RASopathies.

Methods: The study analyzed 76 patients referred to our outpatient clinic over a 6-year period, all of whom were clinically diagnosed with RASopathy and confirmed in most cases by molecular testing. Patient files, clinical photographs, and laboratory results were reviewed and analyzed. A targeted multigene next-generation sequencing panel test was performed, followed by Sanger sequencing for both confirmation and segregation analysis. Multiplex ligation-dependent probe amplification was conducted in a patient with normal sequence results but strong clinical suspicion, to identify potential deletions.

Results: We identified 44 pathogenic, 25 likely pathogenic variants, and 6 variants of uncertain significance based on American College of Medical Genetics and Genomics (ACMG) criteria. Among these, 14 novel variants were found - 13 in the NF1 gene and one in SOS1. NF1 variants were present in 51 cases. Additional variants, likely to represent clinically significant findings, were identified in PTPN11 (n = 11), RAF1 (n = 4), SOS1 (n = 3), RIT1 (n = 3), KRAS (n = 1), NRAS (n = 1), SOS2 (n = 1), and BRAF (n = 1). Diagnoses included 49 patients with NF1, 21 with Noonan syndrome, 2 with neurofibromatosis-Noonan syndrome, 2 with Noonan syndrome with multiple lentigines, and 1 with cardiofaciocutaneous syndrome. Here, 12% of NF1 variants were located in exon 21, 36% of PTPN11 variants in exon 3, and 75% of RAF1 variants in exon 7.

Conclusion: RASopathies have a broad molecular and clinical spectrum, complicating diagnosis and management. Accurate clinical correlation and molecular analysis are essential, as different RASopathy syndromes can result from variants in the same genes, while the same syndrome may arise from different genetic alterations. This study identifies novel variants and emphasizes the need for precise diagnostic approaches in these complex disorders.

Introduction: Type-1 fibrillinopathies, caused by pathogenic variants in the FBN1 gene, show complex genotype-phenotype correlations. Studying these patterns in under-researched populations like Sri Lanka can provide valuable insights into their genetic basis. The objective of this study was to analyse genotype-phenotype correlations in Sri Lankan patients with type-1 fibrillinopathies.

Methods: The genotype and clinical data of all patients undergoing exome sequencing in our centre have been maintained in a database since 2014. In January 2024, this database was searched to identify all patients who were reported to have variants in the FBN1 (NM_000138.5) gene. The genotype and phenotype data of these patients were analysed using bioinformatics tools and standard descriptive statistics.

Results: There were 12 unrelated patients. A total of 6 (50%) were male. Age ranged from 1 to 18 years. All were sporadic and had a distinct heterozygous variant. The phenotype found in these patients together with the associated genotype was as follows: Marfan syndrome - 6 (50%) [c.7487G>C, c.6496G>A, c.4245delT, c.3037G>A, c.2797_2807delTTCAAGTGTCA, c.3472G>A]; MASS syndrome - 5 (41.7%) [c.2926C>T, c.2419G>A, c.5674A>G, c.3338-1G>C, c.3089A>G]; and ectopia lentis syndrome - 1 (8.3%) [c.355T>G]. Four (33.3%) variants were novel. Frameshift and splice-site variants were associated with pronounced skeletal and facial dysmorphic features. However, neonatal region variants did not consistently cause severe disease.

Conclusions: This is the first study to report type-1 fibrillinopathies in the Sri Lankan population. The lack of strong genotype-phenotype correlation suggests the possibility of other genetic modifiers in the Sri Lankan population.