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Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
HHT has an autosomal dominant inheritance. Linkage analysis indicates at least five genes, four of which have been identified. The genes for HHT are located in the transforming growth factor beta (TGF-β) signaling pathway that regulates cell proliferation, differentiation, apoptosis, and migration. Mutations in endoglin or ENG, activin receptor-like kinase or ALK1/ACVRL, and Smad 4, cause JJT1, HHT2, and the combined juvenile polyposis HHT syndrome, respectively. Endoglin and ACVRL1 mutations are seen in roughly 85% of cases. Smad4 mutations are seen in less than 2% of cases. Mutations in bone morphogenetic 9 protein (BMP9 – GDF2 gene) have been reported in some patients. This gene exerts its effects by binding to specific endothelial cell surface receptors, which leads to the association of Smad proteins that regulate gene expression in endothelial cells. Approximately 15% of patients who appear to have HHT clinically do not have identifiable mutations. Additional genes are predicted on chromosome 5 (HHT3) and chromosome 7 (HHT4).
In Situ Gene Insertion for Immunotherapy Using Vaccinia Virus Vectors
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Edmund C. Lattime, Laurence C. Eisenlohr, Michael J. Mastrangelo
The successful induction of a cellular immune response depends upon the interaction of a complex of cytokines, both known and yet to be discovered. For this trial, a vaccinia/GM-CSF recombinant will be evaluated. GM-CSF is a 18-30 kDa monomelic glycoprotein first characterized in the mouse by Burgess et al. (1977). The biology of GM-CSF has been reviewed by Rapoport et al. (1992). The human gene encoding this protein is located on chromosome 5 (Huebner et al., 1985).
Cancer: A Genetic Disease
Published in Jeremy R. Jass, Understanding Pathology, 2020
Solomon et al. (1987) also showed loss of chromosome 5 in the common or non-inherited type of colorectal cancer. This was a crucial observation because it established the role of tumour suppressor genes in a common form of non-inherited cancer. It also showed how other types of rumour suppressor gene could be identified. One merely had to take a series of cancers of one type and see if particular chromosomes were lost on a consistent basis. If this were so, one could surmise that a tumour suppressor gene would be located on that chromosome. This approach has proved to be highly successful in colorectal and other types of cancer, and many tumour suppressor genes are now known to exist. Some such as p53 have been found to play a role in many different types of cancer. Others are more restricted in their distribution amongst the various types of cancer.
Parental germline mosaic transmission of 5p13.2 microduplication in two siblings of a Chinese family
Published in Journal of Obstetrics and Gynaecology, 2022
Qi Tian, Li-Li Xu, Dong-Zhi Li
An ultrasound at 12 weeks’ gestation revealed a single fetus with a crown-rump length of 54 mm and a nuchal translucency of 1.3 mm. Although the parents were explained that the recurrence risk is very low for a de novo duplication, chorionic villous sampling (CVS) was still required by the woman due to the indication of advanced maternal age. Unexpectedly, CNV-seq of the CVS sample detected again the familial 5p13 duplication. The karyotype was 46,XX. The pregnancy was terminated on parents’ request. Parental mosaicism was then considered in this family. The skin tissue of the aborted fetus, combined with the blood samples of the four family members, was sent for further investigation using whole genome sequencing (WGS) for the purpose of precise duplication determination, searching possible single-gene variants and single nucleotide polymorphism (SNP) genotyping. This approach detected a 1.1-Mb duplication on 5p13.2 (HG19:chr5:36,195,246-37,371,079) in the fetus and the male patient, but not in other family members. No potentially causative monogenic variants were detected in the patient. Paternal mosaicism was confirmed by the haplotype analysis of chromosome 5 in this family (Figure 1). Genomic DNA of a sperm sample was obtained from 1 ml semen of the father, and WGS detected a variant allelic fraction of 13. 8%. Thus far, the paternal germline mosaicism origin for the “de novo” duplication was clear.
Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)
Published in Expert Opinion on Investigational Drugs, 2022
Theodora Markati, Gemma Fisher, Sithara Ramdas, Laurent Servais
Spinal muscular atrophy (SMA) is a genetic neuromuscular disease that is characterised by progressive loss of motor neurons leading to progressive muscle weakness, atrophy, and motor and respiratory impairment. The most common form, called 5q-SMA, is caused by a homozygous deletion or loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene on locus 5q13 of chromosome 5, which codes for the homonymous survival motor neuron (SMN) protein [1,2]. 5q-SMA, henceforth called SMA, occurs in 1 in 10,000 live births and it is one of the leading genetic causes of childhood mortality. SMA is characterised by progressive initially proximal and axial muscle weakness, decreased or absent deep tendon reflexes, muscle atrophy, and – in the most severe forms without intervention – bulbar dysfunction and progressive respiratory failure as the cause of early death [3].
Prenatal Diagnosis of 5p Deletion Syndrome with Brain Abnormalities by Ultrasonography and Fetal Magnetic Resonance Imaging: A Case Report
Published in Fetal and Pediatric Pathology, 2020
Didem Kaymak, Verda Alpay, Hakan Erenel, İbrahim Adaletli, Nil Comunoglu, Riza Madazli
Cri du chat syndrome or 5p deletion syndrome, first described by Lejeune and collaborators in 1963, is a clinically recognizable and one of the most common contiguous gene deletion disorder, with an estimated frequency of 1:15,000 to 1:50,000 live births [1]. This syndrome results from a deletion of the short arm of chromosome 5, ranging from the entire short arm to the critical region of 5p15.2 [1]. Clinical features of cri du chat syndrome include, a high-pitched catlike cry, craniofacial dysmorphic features such as round face, micrognathia, hypertelorism, epicanthal folds, low-set ears, abnormal dermatoglyphics, microcephaly and severe psychomotor and developmental delay [2]. The deletion of multiple genes on the distal part of the short arm of chromosome 5 is assumed to be responsible for the phenotype. Although the features of 5p deletion syndrome are well known postnatally, prenatal findings are generally related to abnormal ultrasound findings and few cases have been reported in the literature [3]. We present sonographic features and magnetic resonance imaging (MRI) findings of pontocerebellar hypoplasia, vermis hypoplasia, mild ventriculomegaly, and cortical hypoplasia in a case of prenatally diagnosed 5p deletion syndrome.