Identification Of The Novel Genes For Primary Ciliary Dyskinesia Within Consangiounus Families

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Identification Of The Novel Genes For Primary Ciliary Dyskinesia Within Consangiounus Families

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ABSTRACT

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder reflecting abnormalities in the structure and function of motile cilia and flagella, causing impairment of mucociliary clearance, left-right body asymmetry, and sperm motility. Clinical manifestations include respiratory distress in term neonates, recurrent otosinopulmonary infections, bronchiectasis, situs inversus and/or heterotaxy, and male infertility. Genetic discoveries are emerging from family-based linkage studies and from testing candidate genes. Mutations in 2 genes, DNAI1 and DNAH5, frequently cause PCD as an autosomal recessive disorder. A clinical genetic test has been recently established for DNAI1 and DNAH5, which involves sequencing 9 exons that harbor the most common mutations. This approach will identify at least one mutation in these 2 genes in ›25% of PCD patients. If bial-lelic mutations are identified, the test is diagnostic. If only one mutation is identified, the full gene may be sequenced to search for a trans-allelic mutation. As more disease-caus-ing gene mutations are identified, broader genetic screen-ing panels will further identify patients with PCD. Ongoing investigations are beginning to identify genetic mutations in novel clinical phenotypes for PCD, such as congenital heart disease and male infertility, and new associations are being established between 'ciliary' genetic mutations and clinical phenotypes.

Table of Contents

ABSTRACT2

CHAPTER I: INTRODUCTION4

Normal ultrastructures of cilia and flagella4

Normal ultrastructure of motile cilia4

Normal ciliary beat frequency6

Cilia composition and conservation across species6

Cilia and cilia-related disorders7

Composition of human outer dynein arm complexes8

Composition of human inner dynein arm complexes10

Primary ciliary dyskinesia11

Ultrastructural defects in primary ciliary dyskinesia13

CLINICAL FEATURES14

Early clinical manifestations15

Laterality defects15

Heterotaxy and congenital cardiovascular defects15

Upper respiratory tract16

Lower respiratory tract16

Bronchiectasis: Severity of disease17

Infertility17

Other clinical manifestations18

Genetic heterogeneity: Challenges and methods to identify disease-causing genes18

Dynein axonemal intermediate chain 119

Dynein axonemal heavy chain 519

Dynein axonemal intermediate chain 220

Dynein axonemal heavy chain 1121

Thioredoxin-nucleoside diphosphate22

KTU22

Radial spoke head protein 923

Radial spoke head protein 4A23

Leucine-rich repeat-containing protein 50 (LRRC50)24

Genes associated with abnormal dynein regulatory complex function25

Dynein Light Chain 126

Genes tested and found to be negative in PCD27

PCD co-segregating with other syndromes (OFD1 and RPGR)27

DIFFERENTIAL DIAGNOSIS28

Overview of PCD genetics28

Neonatal respiratory distress30

Laterality defects30

Chronic cough, nasal congestion, and sino-pulmonary disease31

Cystic fibrosis31

Asthma and allergic rhinitis31

Gastroesophageal reflux disease and aspiration32

Immunodeficiency32

Interstitial lung disease (ILD)32

DIAGNOSTIC APPROACH33

DIAGNOSTIC TESTS33

Ultrastructural changes in PCD33

Ciliary motility abnormalities in PCD34

Nasal nitric oxide measurement34

High-Speed Video microscopy36

Mislocalization of axonemal components37

Genetic testing38

Genetic Testing39

Exome-capture and massively parallel sequencing for PCD40

Strategies for further gene identifications41

Novel Therapeutic Options42

Future directions42

AUTOZYGOSITY MAPPING A NOVEL APPROACH FOR GENE IDENTIFICATIO44

Consanguinity and homozygosity mapping44

Mechanism and digital rendering46

Autozygosity and human populations48

Autozygosity mapping for autosomal recessive disorders49

Autozygosity mapping for Complex disorders49

Autozygosity and annotation of human genome; Disease gene mapping51

DNA dispensability55

SNP annotation56

Homozygosity mapping in gene discovery57

CHAPTER I: INTRODUCTION

Normal Ultrastructures Of Cilia And Flagella

Cilia and flagella are evolutionarily ancient organelles whose structure and function have been rigidly conserved across the phylogenetic spectrum. Cilia and flagella are highly complex organelles that are closely related in structure through the bodies of human's protozoa (Chlamydomonas reinhardtiiand Trypanozomabrucei). The cilium is an organelle that arises as a consequence of the basal (centriole) and is present in almost all human ...