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Molecular Diagnosis and Prenatal Diagnosis of Three Monogenic Diseases

Author: DianYan
Tutor: HuangShangZhi
School: Peking Union Medical College , China
Course: Of Medical Genetics
Keywords: Molecular diagnostics Hereditary symmetry Dyschromatosis Collodion glue gentile Eczema - thrombocytopenia Purpura syndrome Prenatal diagnosis
CLC: R714.5
Type: Master's thesis
Year: 2009
Downloads: 44
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Abstract

With an increasing number of virulence genes or candidate genes have been cloned, the relation between gene mutations and diseases has been further elaborated. Simple, rapid, highly sensitive and well specific, low cost, automatic, accessible in high through put for gene mutation detection systems are on the urgent need for clinical use, in genetic diagnosis of the patients, carrier detection and prenatal diagnosis for high-risk fetus. There are a variety of methods used for detection of gene mutation currently. The design of this subject was to utilize combinely the most common methods that be used for molecular diagnosis of monogenic disease. That is, from clinical diagnosis of a certain monogenic disease, to literature reviewing, selecting the candidate genes, designing the primers, PCR amplication, sequencing, identifying the pathogenic mutations, and finally, after the pathogenic mutations were identified in the family, custom prenatal diagnosis can be offered to the pregnancy at risk in the family.This topic covers the following three monogenic diseases:1. Dyschromatosis symmetrical hereditaria （DSH）.DSH is a rare autosomal dominant hereditary skin disease characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the face and the dorsal aspects of the extremities. The pathogenic gene is the RNA-specific adenosine deaminase （ARAD） gene. We used the above strategy in the analysis of the pedigree and identified a single nucleotide deletion （c.1642 delC, p.Pro548GlnfsX15） in exon3 of ADAR gene in the patients, and the mutation was not detected in the normal family members and in any of the control individuals. This single nucleotide deletion was responsible for the disease in the family and it was a novel pathogenic mutation not reported previously.2. Collodion baby.It is a specific congenital ichthyose. It has strong genetic heterogeneity, and many virulence genes involved. Based on a variety of reasons, we suspected the baby was affected with Lamellar ichthyosis （LI） or nonbullous congenital ichtyosiform erythroderma （NBCIE）, and we selected the transglutaminase 1（TGM1） gene as the candidate gene. We identified three new alternations in TGM1 gene of the proband, a single nucleotide deletion c.694delG （p.Glu232SerfsX98） in exon4, a missense mutation C.463C>T （p.Arg155Trp） in exon3 and a nonsense mutation c.578G>A （p.Trp193X） in exon4. The missense mutation was not detected in his father and in any of the control individuals by AS-PCR. Transmission analysis showed that the father was heterozygous for c.694delG mutation, while the mother carried the two mutations （c.463C>T and c.578G>A）. The c.578G>A （p.Trp193X） was a causal mutation itself and the C.463C>T （p.Arg155Trp） mutation might be causative also. Two causal mutation located on the same allele might caused by repeat mutation, not by conversion.3. Wiskott-Aldrich syndrome （WAS）.WAS is an X-linked recessive hereditary immuno- deficiency disease. It is characterized by eczema, thrombocytopenia and infection. The specific diagnosis is based on the finding of small size of platelets. A double-nucleotide-deletion （c.107₁08delTT, p.Phe35X） was identified in exonl of WASP gene in the proband and his mother. This mutation has been reported. When the mother was in pregnancy again, custom prenatal diagnosis was performed in the request of the family. The fetus was a female and got the normal allele from the mother.

Molecular Diagnosis and Prenatal Diagnosis of Three Monogenic Diseases

Abstract

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