Molecular Syndromology最新文献

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.

Introduction: Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients.

Case presentation: Whole exome sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in TCF12 (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3), was identified in the proband, along with a novel likely pathogenic variant in SMARCA2 (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis.

Conclusion: This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.

Background: Galactosialidosis (GS) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTSA gene. The resulting deficiency of protective protein/cathepsin A leads to reduced β-galactosidase and α-neuraminidase activity, causing multisystem involvement. While typical features include dysmorphic facies, organomegaly, skeletal dysplasia, and neurological impairment, dermatologic manifestations remain poorly characterized.

Case presentation: We report a 9-month-old girl presenting with hepatosplenomegaly and diffuse dermal melanocytosis. Her history included nonimmune hydrops fetalis, congenital cataract, developmental delay, and recurrent respiratory infections. Clinical and radiological evaluation revealed coarse facial features, dysostosis multiplex, and periventricular white matter changes. Enzyme assay demonstrated markedly reduced β-galactosidase activity. Genetic testing identified a homozygous CTSA c.359T>C (p.Ile120Thr) variant, classified as likely pathogenic. Family screening revealed her 10-year-old brother carried the same variant in homozygosity. He exhibited milder features, including developmental delay, hearing loss, and skeletal abnormalities without cutaneous involvement or organomegaly. Enzymatic deficiency was confirmed in both siblings.

Conclusion: This report highlights diffuse dermal melanocytosis as a possible novel cutaneous marker of GS, potentially aiding early recognition. It also illustrates intrafamilial phenotypic variability despite identical genotypes. Our findings underscore the importance of dermatologic clues in the diagnostic workup of lysosomal storage disorders and advocate for family-based genetic screening to identify asymptomatic or mildly affected individuals.

Background: Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder spectrum, with phenylketonuria (PKU) being the most common, caused by PAH gene variants in an autosomal recessive inheritance form. Genetic differences significantly influence phenotypical outcomes in HPA patients. This study investigates the genotype-phenotype correlation of HPA patients, aiming to evaluate treatment consistency based on specific genotypes and demonstrate that genotyping can provide guidance for optimal treatment.

Methods: Genomic DNA was obtained from 50 PKU, 2 tetrahydrobiopterin (BH4) deficiency, and 1 dihydropteridin reductase deficiency patients for next-generation sequencing of HPA-associated genes. Variants were analyzed using the Sophia DDM program, dbSNP, ClinVar, Ensembl information services, and ACMG 2015 criteria. Allelic phenotypical values consistent with enzyme functionality based on literature data were assessed using anamnesis information.

Results: Carriers of two null variants (homozygous/compound heterozygous) were unresponsive to BH4 therapy, reflecting the existing literature. Notably, BH4 therapy was also inadequate for two PKU patients who were compound heterozygous carriers with one null variant (P3, P10), even with other variants assumed protein function (PAH [NM_000277.3] c.1289T>C, c.143T>C). However, PAH variants c.1169A>G (P21) and c.898G>T (P25) demonstrated positive BH4 responses when compounding a null variant, along with a c.782G>A homozygous patient benefiting from BH4. Two novel variants were observed in PTS and QDPR genes, respectively.

Conclusion: This study implies that genetic testing is plausible in predicting pretreatment BH4 testing outcomes, aiding in decision-making before patient evaluation, and providing valuable guidance to metabolism specialists during HPA treatment. With more HPA genotypes analyzed and clinical data published, genotyping will hold a better deterministic position toward patient prognosis and therapeutic management.

Introduction: Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders. NDDs caused by rare gene mutations are referred to as Rare Genetic Neurodevelopmental Syndromes (RGNS). Witteveen-Kolk syndrome (WITKOS) is such a RGNS, caused by heterozygous mutations in SIN3A and characterized by developmental problems, facial dysmorphisms, short stature, brain abnormalities, intellectual disability, and behavioral problems. Care for individuals with WITKOS mainly focuses on somatic characteristics. To address this issue, we present a case study of the first documented treatment of behavioral problems in WITKOS.

Case presentation: The patient is a 27-year-old single female with known developmental problems during childhood and a history of severe psychiatric problems. She received the genetically confirmed diagnosis of WITKOS at the age of 25 and based upon extensive intellectual and neuropsychological examination, a personalized psychological treatment could be performed. This treatment consisted of twelve individual sessions aimed to reduce anxiety, fatigue and thought disorder by treating factors contributing to cognitive overload. Evaluation during treatment and at 3-month follow-up showed a positive increase in functioning and acceptance as well as the acceptance of successive follow-up treatment. However, she was unable to maintain favorable changes in emotion-regulation strategies at follow-up, emphasizing the need for prolonged professional guidance and support.

Conclusion: Neurocognitive evaluation enabled the adaptation of treatment strategies to the patients developmental and neurocognitive functioning, provided guidance in treatment choice, supported the rewriting of her personal narrative and resulted in successive care.

Background: HERC2 encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of HERC2-related disorders, including an unusual cardiac manifestation.

Case presentation: The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the HERC2 gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy.

Conclusion: These patients underscore the importance of recognizing novel clinical features associated with the HERC2 LoF variants, which can guide disease characterization and patient management.