Molecular Syndromology最新文献

Introduction: Prior research on the genotype and allele variations of immunometabolism genes and their correlations with the risk of myeloproliferative neoplasms (MPNs) and chronic myeloid leukemia (CML) is inconsistent.

Aim: This study aimed to assess the correlations between mutations in specific immunometabolism genes with the risk and progression of MPN and CML in Saudi patients.

Methods: This case-control study included 244 Saudi patients, 122 patients with MPNs and CMLs, and 122 healthy controls. Immunometabolism genes, including BCL3 (rs2927488 G>A), MDM4 (rs11801299 G>A), KLF14 (rs972283 G>A), and miR-146a (rs2910164 C>G), were identified via tetra amplification-refractory mutation system PCR.

Results: In comparison to healthy persons, MPN and CML patients exhibited a higher prevalence of genotype and allele variants in immunometabolism genes, BCL3 rs2927488 G>A (0.027), MDM4 rs11801299 G>A (0.028), KLF14 rs972283 G>A (0.0004), and miR-146a rs2910164 G>C (0.004).

Discussion and conclusion: The prevailing inheritance model suggested that mutations in all four immunometabolism genes were significantly correlated with an elevated chance of developing MPNs, with increases of 1.84-, 2-, 4.28-, and 2.75-fold for BCL3, MDM4, KLF14, and miR-146a, respectively, in comparison to healthy controls. In addition, we assessed the effect of gene polymorphisms on the course of the disease, and rapid disease progression was found to be correlated with the presence of these polymorphisms. These findings could help determine the risk of developing MPNs and patient prognosis.

[This corrects the article DOI: 10.1159/000540570.].

Introduction: RASopathies are genetic disorders linked to the RAS/MAPK signaling pathway, including Noonan syndrome and related conditions. These disorders have overlapping features and variable phenotypes, making diagnosis challenging. This study examines the clinical and genetic characteristics of RASopathies in pediatric patients to improve diagnostic accuracy and identify novel pathogenic variants.

Methods: A total of 23 patients, who were not related to each other and were clinically diagnosed with RASopathy, participated in the study. Patients underwent next-generation sequencing (NGS) panel analyses of 14 RASopathy genes.

Results: Pathogenic variants were found in 18 out of 23 patients (78%). The most common variants were in PTPN11 and SOS1. Novel variants were identified in KRAS and NF1 expanding the known genetic spectrum. Frequent clinical features included distinctive facial features, growth delays, and heart defects, notably pulmonary stenosis. Intellectual disability was more common in patients with PTPN11 variants, while SOS1 variants were associated with unique features such as previously unreported polydactyly and choanal atresia.

Conclusion: Targeted NGS panels improve diagnosis of RASopathies, with a variant detection rate of 78%. Including the NF1 gene, even without signs of neurofibromatosis, enhances diagnostic success. This study adds to our understanding of genotype-phenotype relationships in RASopathies and highlights new clinical features tied to SOS1 variants. Comprehensive genetic testing supports earlier and more personalized care for patients with RASopathies.

Introduction: Cobalamin J disease (CblJ) is an ultrarare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic academia and homocystinuria (MAHCJ; 614857).

Case presentation: A new patient with MAHCJ, representing the eighth documented instance, is reported here. A novel homozygous missense variant c.1591C>T (p.Arg531Trp) in exon 17 of ABCD4 (NM_005050.4) was identified. The patient, a 15-year-old male of Azerbaijani descent, presented with severe abdominal pain beginning at the age of 1 year. These episodic pain attacks were accompanied by hypotonia, pallor, nausea, and vomiting. Initial evaluations were inconclusive. At the age of 8 years, the patient developed megaloblastic anemia due to vitamin B12 deficiency, leading to the initiation of replacement therapy. The pain attacks ceased during treatment but recurred whenever vitamin B12 levels dropped after discontinuation. The patient exhibited no dysmorphology, skin hyperpigmentation, somatic abnormalities, seizures, or neurodevelopmental delays and remains in remission with ongoing vitamin B12 treatment.

Discussion: This patient is the oldest diagnosed with MAHCJ and has the longest documented clinical course. This report expands the known clinical and molecular spectrum of this rare disease. We recommend remembering cobalamin defects in the differential diagnosis of unresolved abdominal pain attacks.

Introduction: Interstitial deletions in 3p21.31 are rare and have been associated with developmental delay, intellectual disability, and facial dysmorphism. To our knowledge, there are no reported individuals with a 3p21.31 interstitial deletion associated with aortic root dilatation.

Case presentation: We report a 2-year-old girl with 3p21.31p14.3 deletion, aortic root dilatation, global developmental delay, hypotonia, and distinctive facial features. The size of this interstitial deletion is 6.8 Mb and it encompasses 120 genes. None of these genes have a known association with aortic complications. A custom gene panel of 37 genes associated with familial thoracic aortic aneurysm did not identify a known monogenic cause of aortic dilatation in this individual.

Conclusion: This case represents an expansion of the phenotypic spectrum associated with 3p21.31 deletions, highlighting the novel association with aortic root dilatation. Further studies are needed to explore potential mechanisms linking this chromosomal deletion to vascular complications.

[This corrects the article DOI: 10.1159/000545192.].

Introduction: Nager acrofacial dysostosis (#154400) is a rare and mostly sporadic malformation syndrome characterized by craniofacial and extremity findings. In the study, a new case diagnosed in the neonatal period will be presented.

Case presentation: The neonatal intensive care unit consulted with our pediatrics genetic clinic for a 2-week-old male patient, who was being followed up in their unit, due to his dysmorphic findings and extremity defects. In the physical examination, downward palpebral fissures, zygomatic bone hypoplasia, mandibular hypoplasia, retromicrognathia, bilateral microtia, bilateral external auditory canal atresia, and bilateral thumb agenesis were observed. Direct radiographs showed left radius hypoplasia and bilateral thumb agenesis. Nager syndrome was considered in the presence of typical craniofacial findings, preaxial extremity deformities, and radiological findings. In the SF3B4 sequence analysis, c.737dupC p.(V247Sfs*239) heterozygous variant was detected.

Conclusion: As a result of the segregation analysis, it was demonstrated that the variant was de novo. Nager acrofacial dysostosis should be considered in the patients with craniofacial malformations and radial ray findings.

Introduction: Complex chromosomal rearrangements (CCRs) are constitutive structural aberrations involving three or more chromosomal breaks on three or more chromosomes resulting from complex events such as fork stalling and template switching, microhomology-mediated break-induced repair, or breakage-fusion-bridge cycles.

Case presentation: Here we report an 11-year-old female that was referred to our outpatient clinics for learning disability and dysmorphic features. Due to clinical findings, karyotype analysis was done initially, and a CCR involving five chromosomes was detected. Fluorescence in situ hybridization (FISH) analysis and chromosomal microarray analysis were done subsequently. Balanced translocations were observed between chromosomes 1, 5, 7, and 10, a balanced paracentric inversion of chromosome 2, and two interstitial deletions in the long arm of the chromosome 5. Optical genome mapping was done to further investigate this exceptional CCR and a paracentric inversion that was associated with the two interstitial deletions was detected in the long arm of chromosome 5.

Conclusion: Molecular cytogenetic techniques, such as microarray and FISH, are essential for detecting copy number variations at CCRs that appear to be balanced by karyotyping. Nonetheless, optical genome mapping enhances the resolution offering a valuable complement to traditional cytogenetic techniques.

Introduction: Gorlin syndrome (GS) is a rare autosomal dominant condition that predisposes to cutaneous basal cell carcinomas, jaw keratocysts, and skeletal anomalies. Most patients with GS have a heterozygous pathogenic variant in the PTCH1 gene, although a minor subset have a pathogenic variant in the SUFU gene.

Case presentation: We report a 34-year-old woman meeting clinical diagnostic criteria for GS and with an affected father who also meets diagnostic criteria. Both had a novel germline splice-region variant that was originally classified as a variant of uncertain significance.

Conclusion: We used cDNA analysis to provide additional evidence to allow re-classification of the non-canonical splice variant and provide a formal genetic diagnosis that can also be used for family planning and to screen at-risk relatives.

Introduction: Truncus arteriosus (TA) is a life-threatening cardiovascular anomaly involving a ventricular septal defect and a common ventricular outflow tract. Recently, biallelic variants in TMEM260 have been identified as causative for structural heart defects and renal anomalies syndrome (SHDRA, MIM 617478), which includes TA. Approximately 30 patients with SHDRA have been reported, but the genotype-phenotype correlation remains unclear. Founder variants have been identified in patients of East Asian and Ashkenazi Jewish ancestry.

Case presentation: The male infant, the third child of unrelated Japanese parents, was prenatally diagnosed with TA via detailed ultrasound examination. His older sister also had TA and died at 20 days of age. Despite intensive cardiorespiratory care, the patient passed away at 53 days due to heart failure. Genetic analysis identified a homozygous deletion of TMEM260 exons 6 and 7, resulting from a 7,066-bp deletion with a 1 bp insertion, inherited from heterozygous parents. This deletion is included in the structural variation dataset with an allele frequency of 0.00173 (29/8,380) in ToMMo 8.3K JPN-SV.

Discussion: This is the first familial TA caused by a biallelic structural variation in TMEM260. The 7,066-bp deletion shows a high allele frequency in the Japanese population. These findings support the idea that this TMEM260 deletion may be a significant cause of TA and should therefore be considered alongside the previously known c.1617del variant as a potential causative factor.