Molecular Syndromology最新文献

Introduction: Chronic haemolytic anaemia, increased susceptibility to infections, cardiomyopathy, neurodegeneration, and death in early childhood are the clinical findings of triosephosphate isomerase (TPI) deficiency, which is an ultra-rare disorder. The clinical and laboratory findings and the outcomes of 2 patients with TPI deficiency are reported, with a review of cases reported in the literature.

Case presentation: Two unrelated patients with haemolytic anaemia and neurologic findings who were diagnosed as having TPI deficiency are presented. Neonatal onset of initial symptoms was observed in both patients, and the age at diagnosis was around 2 years. The patients had increased susceptibility to infections and respiratory failure, but cardiac symptoms were not remarkable. Screening for inborn errors of metabolism revealed a previously unreported metabolic alteration determined using tandem mass spectrometry in acylcarnitine analysis, causing elevated propionyl carnitine levels in both patients. The patients had p.E105D (c.315G>C) homozygous mutations in the TPI1 gene. Although severely disabled, both patients are alive at the ages of 7 and 9 years.

Discussion: For better management, it is important to investigate the genetic aetiology in patients with haemolytic anaemia with or without neurologic symptoms who do not have a definitive diagnosis. The differential diagnosis of elevated propionyl carnitine levels using tandem mass spectrometry screening should also include TPI deficiency.

Background: Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension. Pulmonary arterial hypertension (PAH) and PVOD/PCH are clinically similar, but there is a risk of drug-induced pulmonary edema when PCH patients receive the PAH therapy. Therefore, early diagnosis of PVOD/PCH is important.

Objectives: We report the first case in Korea of PVOD/PCH in a patient carrying compound heterozygous pathogenic variants in the EIF2AK4 gene.

Case description and method: A 19-year-old man who was previously diagnosed with idiopathic PAH suffered from dyspnea on exertion for 2 months. He had a reduced lung diffusion capacity for carbon monoxide (25% predicted). Chest computed tomography images showed diffusely scattered ground-glass opacity nodules in both lungs with an enlarged main pulmonary artery. For the molecular diagnosis of PVOD/PCH, whole-exome sequencing was performed for the proband.

Results: Exome sequencing identified two novel EIF2AK4 variants, c.2137_2138dup (p.Ser714Leufs*78) and c.3358-1G>A. These two variants were classified as pathogenic variants according to the 2015 American College of Medical Genetics and Genomics guidelines.

Conclusions: We identified two novel pathogenic variants (c.2137_2138dup and c.3358-1G>A) in the EIF2AK4 gene. Identification of possible pathogenic gene variants by whole-exome sequencing or panel sequencing is recommended as a guide to adequate treatment of patients with pulmonary hypertension.

Introduction: Hypospadias is a malformation of the genitourinary system in males, characterized by the placement of the urethral opening in the ventral surface of the penis. Although controversies continue about etiology, endocrine disrupting chemicals that disrupt normal endocrine signaling at the receptor or signal transduction level are thought to play an essential role in etiology. This study aimed to investigate the receptor gene expressions of the sex hormones and FGFR2, HOXA13, and TGFB1, which are considered to play an essential role in developing hypospadias.

Methods: The samples from the foreskin of 26 patients with hypospadias and 26 healthy children who underwent circumcision operations were collected. ESR1, AR, FGFR2, HOXA13, and TGFB gene expressions were investigated by real-time PCR in samples obtained during surgery.

Results: In the hypospadias group, ESR1 expression was increased (p = 0.013), and AR and FGFR2 expressions were decreased, which were found to be statistically significant (p = 0.027 and p = 0.003, respectively). There was no statistically significant difference between hypospadias and control groups in TGFBand HOXA13expression levels (p > 0.05).

Discussion: The results suggest that sex hormone receptors and FGFR2 may play an essential role in developing male external genital structures at the gene level. The defects in the expression of these genes can contribute to understanding the development of hypospadias.

Introduction: Syndactyly is a common congenital limb malformation. It occurs due to embryological failure of digit separation during limb development. Syndactyly often runs in families with an incidence of about one out of every 2,500-3,000 live births.

Methods: Here, we have reported two families presenting features of severe forms of syndactyly. The disorder segregated in autosomal recessive in one and in autosomal dominant manner in the second family. Search for the causative variants was carried out using whole-exome sequencing in family A and candidate gene sequencing in family B.

Results: Analysis of the sequencing data revealed two novel missense variants, including p.(Cys1925Arg) in MEGF8 in family A and p.(Thr89Ile) in GJA1 in family B.

Conclusion: In conclusion, the novel findings, presented here, not only expand the mutation spectrum in the genes MEGF8 and GJA1, but this will also facilitate screening other families carrying similar clinical features in the Pakistani population.

Introduction: Brittle cornea syndrome (BCS) is a rare connective tissue disorder with ocular and systemic features. Extreme corneal thinning and fragility are the main hallmarks of BCS.

Case report: A 4-year-old boy presented with recurrent spontaneous corneal perforation. He had blue sclera, corneal leucoma, irregular iris, shallow anterior chamber, corneal astigmatism, and bilateral corneal thinning. He also had several systemic features including hearing loss, skin hyperelasticity, joint hypermobility, scoliosis, and umbilical hernia. A diagnosis of BCS was confirmed with molecular analysis. A homozygous c.17T>G, p.(Val6Gly) variation was identified in the PRDM5 gene.

Discussion: p.(Val6Gly) variation in PRDM5 was previously reported in 2 patients with BCS. We also considered PRDM5 c.17T>G, p.(Val6Gly) variation as pathogenic based on the following features: the absence of the variation in population databases, in silico predictions, segregation analysis, and clinical signs of our patient. Extremely thin and brittle corneas lead to corneal perforation spontaneously or after minor trauma. Nearly all patients have lost their vision because of corneal rupture and scars. The key challenge in the management of BCS is the prevention of ocular rupture which relies on early diagnosis. Early diagnosis allows for taking prompt measures to prevent ocular rupture.

Introduction: Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fractures and low bone mass. Recently, mutations of the WNT1 gene have been reported to be causative in OI. The mutation in WNT1 causes autosomal-recessive OI due to its critical role in bone formation. WNT1 mutations cause varying degrees of clinical severity, ranging from moderate to progressively deforming forms. In addition to the OI phenotype, our cases also had extra-skeletal findings.

Case presentation: We describe two siblings with multiple fractures and developmental delay. A novel homozygous frameshift WNT1 mutation was detected in this family, and we reviewed the literature for WNT1-related OI cases.

Discussion: We report a novel variant with a clinical diagnosis of severe OI, and this review will provide a comprehensive overview of previously published cases of OI type XV. With a better understanding of disorders associated with WNT1 mutations, therapies targeting Wnt1 signaling pathway may contribute therapeutic benefits.

Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement.

Case presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD.

Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

Introduction: Congenital disorders of glycosylation (CDG) are autosomal recessive hereditary genetic disorders characterized by abnormal glycosylation of N-linked oligosaccharides.

Case presentation: In this research, prenatal testing (24th week of pregnancy) revealed findings like polyhydramnios, hydrocephaly, abnormal facial features/shape, brain morphology abnormality, spina bifida, vertebral column abnormality, macrocephaly, scoliosis, micrognathia, abnormal kidney morphology, short fetal femur length, and short fetal humerus length in the fetus. Whole-exome sequencing was performed; the COG5 gene has shown a pathogenic variant.

Discussion: Homozygous patients have never been seen before in the literature for COG5-CDG. We demonstrate the first CDG patient at fetus stage with homozygous COG5 c.95T>G variant.