Molecular Syndromology最新文献

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.

Background: The aim of this study was to determine genetic syndromes including both cancers and intellectual disabilities, specific cancer types accompanying intellectual disabilities.

Summary: We obtained the data from the clinical synopsis of the syndromes available in the OMIM database (https://www.omim.org/). In the first step, we detected 794 syndromes using different terms of intellectual disabilities and cancers. In the second step, we investigated the clinical synopsis of each syndrome in detail. Of these, we included 99 syndromes in which both intellectual disability and any type of cancer were presented. In the third step, we collected following data of these 99 syndromes: OMIM number, gene and location, syndrome/protein, tumor/neoplasia, inheritance, growth, head/neck, respiratory, cardiovascular, abdomen, genitourinary, skeletal, skin/nails/hair, neurologic, endocrine features, immunology, prenatal manifestations, laboratory abnormalities, and other system findings.

Key messages: The most common cancer types among these 99 syndromes are listed in percentage. Since individuals with intellectual disabilities have difficulty expressing themselves and understanding the symptoms of the disease, the diagnosis of diseases in these people is late and their treatment becomes difficult. We suggest that genetic tests to be performed in intellectual disability are important for early diagnosis, follow-up, and treatment of accompanying cancers. We especially emphasize the importance of leukemia, brain tumors, and tumors of embryonal origin in individuals with intellectual disability.

Introduction: Pathogenic variants in the KMT5B gene, encoding a lysine methyltransferase involved in chromatin remodeling, have been associated with intellectual disability, autism spectrum disorder, and various craniofacial features. However, the detailed genotype-phenotype correlations have yet to be fully elucidated.

Case presentation: We report a four-year-old male patient who presented with developmental delay, impaired social interaction, repetitive behaviors, and language delay. Whole-exome sequencing identified a novel heterozygous frameshift variant in KMT5B (c.618del; p.Glu206Aspfs*7). Segregation analysis revealed that the patient's father also carried the same variant and exhibited intellectual disability and obsessive-compulsive disorder.

Conclusion: By presenting a novel KMT5B variant alongside an atypical adult neuropsychiatric presentation, this report broadens both the variant and phenotypic spectrum of KMT5B haploinsufficiency. It further underscores the potential for neurobehavioral manifestations to extend beyond childhood, advocating for sustained clinical surveillance and age-spanning neuropsychiatric assessment.

Introduction: VACTERL association (VA) is defined as the nonrandom co-occurrence of at least three of the following six features: Vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The genetic basis of VA remains undiscovered.

Case presentation: In this study, we report a 22-year-old male patient suspected of VA at birth (TE: esophageal atresia (EA), C: dextrocardia, without heterotaxy, and L: hypoplasia of thumb phalanges). Additionally, the patient presented lacrimal gland aplasia, xerostomia, and pulmonary hypoplasia (PH). Whole exome sequencing identified a novel loss-of-function FGF10 variant: c.2T>C; p.(Met1Thr). Pathogenic variants in the FGF10 gene are known causes of lacrimo-auriculo-dento-digital syndrome 3 or aplasia of lacrimal and salivary glands, but their association has been scarcely described in the literature. This FGF10 variant was also detected in other family members exhibiting a wide range of clinical variability; however, PH and EA were observed only in our index case.

Conclusion: This report supports the involvement of the FGF10 gene in EA and PH, and expands the phenotypic spectrum of pathogenic FGF10 variants. We hypothesize that while FGF10 contributes to the development of PH or VACTERL association (VA), a yet unidentified second hit is likely necessary.

Background: Double genetic diagnoses are increasingly identified with the advent of genome-wide sequencing techniques. While MECP2 mutations are associated with Rett syndrome and EPHB4 mutations with vascular malformation syndromes, their co-occurrence has not been previously described.

Case presentation: We describe an 8-year-and-2-month-old girl presenting with global developmental delay, autism spectrum disorder, and stereotypic behaviors, along with multiple well-demarcated cutaneous vascular lesions. Although she had no clinical seizures, electroencephalogram revealed epileptiform discharges. Physical examination showed dysmorphic features and vascular anomalies, including telangiectatic pink-to-red macular vascular lesions. Whole exome sequencing (WES) identified two de novo heterozygous pathogenic variants: a missense mutation in MECP2 (c.433C>T; p.Arg145Cys), a gene classically implicated in Rett syndrome, and a nonsense mutation in EPHB4 (c.1093C>T; p.Arg365Ter), which has been previously associated with capillary malformation-arteriovenous malformation syndrome type 2. The neurodevelopmental findings, while consistent with the broader spectrum of MECP2-related disorders, along with coexisting vascular anomalies, were best accounted for by a dual genetic diagnosis involving both MECP2 and EPHB4.

Conclusion: This case underscores the diagnostic value of considering dual genetic diagnoses in patients with complex phenotypes and highlights the role of WES in uncovering multilocus variation, thereby expanding the known phenotypic spectrum associated with MECP2 and EPHB4 mutations.

Introduction: Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive-inherited disorder of amino acid metabolism known as glycine encephalopathy. Clinical manifestations arise because of the enzyme deficiency involved in glycine degradation. Currently, no effective treatment exists to alter the prognosis of NKH; available therapies focus primarily on reducing glycine accumulation in the body. MicroRNAs (miRNAs) are small noncoding RNAs that function as transcriptional and post-transcriptional regulators of gene expression. Here, we report the comparative profiling of small RNA sequencing (RNA-seq) data generated from clinical samples diagnosed with a specific condition.

Methods: We identified miRNAs using miRNA-seq with samples obtained from three NKH patients, five individuals with heterozygous variants in NKH genes, and seven control cases. Utilising pathways from the PubChem database, we identified NKH-related pathways and used bioinformatics tools for miRNA, pathway, and disease prediction. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to enrich the predicted target genes of differentially expressed miRNAs based on miRNA-target interactions.

Results: In our study, 10 known miRNAs were identified to be associated with NKH using at least two different tools. Our study is the first to demonstrate altered miRNA profiles in cases where the expression of AMT and GLDC genes is reduced.

Conclusion: NKH is an ultrarare and difficult-to-diagnose disease. This study determines the miRNA-based biomarkers for early detection of NKH and provides a robust framework for advancing future experimental research and diagnostic strategies.