Molecular Syndromology最新文献

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.

Introduction: Combined oxidative phosphorylation deficiency 4 (COXPD4, OMIM #610678) is a very rare mitochondrial disorder caused by biallelic variants in TUFM gene. The condition is characterized by microcephaly, severe early-onset lactic acidosis, and progressive, often fatal, infantile encephalopathy. To date, only 8 patients with biallelic TUFM variants have been reported.

Case presentation: We present a case of a female infant with microcephaly who died from severe lactic acidosis at 7 months of age. Genetic analysis revealed homozygous c.1016G>A (p.Arg339Gln) variant in the TUFM gene, which has previously been reported in three other COXPD4 cases. This is the fourth publication describing the same variant in this rare disorder, suggesting that it is a recurrent variant in COXPD4 patients.

Conclusion: Arg339Gln variant was found in all patients from Turkey and is considered a potential founder mutation. This report aims to contribute to the phenotypic spectrum of COXPD4, explore the frequency and clinical presentation of the reported variants, enhance the understanding of genotype-phenotype correlations, and raise awareness of rare mitochondrial disorders.

Introduction: Cerebro-oculo-nasal syndrome (CONS) is characterized by ocular alterations ranging from anophthalmia/microphthalmia to normal eyes, structural anomalies of the central nervous system, and proboscis-like nares. This syndrome was first described more than 30 years ago, but only 21 patients have been reported to date.

Case presentation: In the present report, we present a 20-year-old CONS patient who exhibited anophthalmia, microphthalmia, cleft lip-palate, and proboscis-like nares. Exome sequencing (ES) analysis was performed for clinical diagnosis for the index case; her parents were evaluated with Sanger sequence analysis methods in terms of the variation detected in the index case. The ES analysis of the patient identified a novel heterozygous frameshift variant in the ZNF185 gene. This variant was not detected in her parents, whose biological relationship to the patient was confirmed through identity testing. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this novel de novo variant was assessed as likely pathogenic. Peripheral blood mononuclear cells were isolated from peripheral blood of the patient and her parents. Protein was extracted and analyzed by Western blot using antibodies against ZNF185 and GAPDH as control. Western blot analysis detected an ∼80 kDa protein in both the patient and her healthy parents. Additionally, extra bands (∼20-25 kDa) were observed in the patient using the anti-ZNF185 antibody.

Conclusion: We aimed to evaluate all CONS patients based on their clinical features. Furthermore, we propose that the ZNF185 gene may play a role in the etiology of CONS.

Introduction: Witteveen-Kolk syndrome (WITKOS, OMIM 613406) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in the SIN3A gene or microdeletions involving SIN3A at 15q24. We aimed to present new clinical and genetic findings of 2 patients diagnosed with WITKOS.

Case presentation: This study presents 2 cases: patient 1 had genomic variations caused by a multilocus disease, including pathogenic variations in the SIN3A gene and paternal mosaic uniparental disomy 11 (UPD(11)p), and showed syndromic symptoms. Patient 2 was followed up with a preliminary diagnosis of hypogonadotropic hypogonadism (HH) and a new de novo pathogenic variation in the SIN3A gene.

Conclusions: These findings expand the phenotypic spectrum associated with SIN3A variants and highlight the importance of comprehensive genetic testing in atypical presentations of rare diseases. The inclusion of SIN3A in HH gene panels may aid molecular diagnosis in cases without apparent syndromic findings. This study contributes to the understanding of the phenotypic and genotypic heterogeneity of WITKOS.

Background: Lesch-Nyhan disease (LND) is characterized by severe motor problems, self-injury, and gout. LND is caused by loss of function of HPRT which functions to salvage purine nucleotides, but the link between purine recycling and the neurological phenotypes remains unknown. One-carbon metabolism (OCM) is the utilization of single-carbon units for important cellular pathways such as de novo purine synthesis, the methionine cycle, and the transsulfuration pathway. Since purine salvage is lost in LND and one-carbon groups are required for de novo purine synthesis, there is an obligate need to re-route one-carbon flux in LND. Midbrain dopaminergic neurons have been associated with LND and may represent an important intersection point for OCM and LND.

Summary: In this review, we analyze the relationships between HPRT loss, OCM, and the unique metabolic features of midbrain dopaminergic cells. Our hope is to better understand how changes to metabolic flux in OCM might affect midbrain dopaminergic cells and ultimately lead to the neurological phenotypes of LND.

Key messages: OCM provides important components for different processes and pathways including de novo purine synthesis, methionine cycle, transsulfuration pathway, and polyamine synthesis. Changes in flux toward de novo purine synthesis in LND may affect these interconnected processes and have potential effects on dopaminergic cells as discussed in this review.

Introduction: This study aimed to identify the potential genetic defects underlying familial clustering of lens dislocation in two unrelated Turkish families, consistent with the clinical features of isolated ectopia lentis (IEL). The investigation seeks to determine whether the detected findings overlap with those observed in other syndromic conditions that present with lens dislocation. Additionally, a focused review of IEL within the scientific literature was conducted to contextualize the molecular and phenotypic spectrum associated with lens abnormalities. The results of this study are expected to contribute to a deeper understanding of the molecular basis of IEL and to enhance diagnostic precision, genetic counseling, and clinical management strategies for affected individuals.

Case presentation and conclusion: Comprehensive family histories and clinical evaluations revealed lens dislocation and associated ocular manifestations without systemic abnormalities or extraocular features suggestive of connective tissue disorders. Whole-exome sequencing (WES) in affected individuals identified two heterozygous FBN1 missense variants. The first variant, ENST00000316623.5:c.2920C>T, which has been previously reported in the literature, is located within the TB5 domain and was identified in ten affected members of family 1. The second variant, ENST00000316623.5:c.7018T>C, located within the TB9 domain, was identified in a single affected individual from family 2 and is reported here for the first time in association with IEL. Segregation analysis demonstrated that both variants co-segregated with the ectopia lentis phenotype and were completely absent in unaffected family members as well as in WES data from 200 ophthalmologically normal in-house controls. Besides, our study focused review of the literature on FBN1-associated IEL revealed that approximately 66.7% of reported variants involve missense substitutions affecting cysteine residues. Our study further reinforces this pattern by identifying two rare FBN1 missense variants that co-segregate with the phenotype, thereby expanding the known mutational spectrum of IEL. These findings also underscore the phenotypic heterogeneity of IEL, as reflected by the variable age of onset among affected individuals, and emphasize the critical role of domain-specific cysteine-altering mutations in the pathogenesis of IEL.