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Uncloned, Mapped Autosomal Mendelian Disorders

Initiative Rationale

This area is intended to aid investigators that have mapped Mendelian disorders to intervals of about 10 Mb or less, but can not make further progress due to lack of additional patients to narrow the region or lack of access to sufficient sequencing capacity to sequence a large region. The major justification for this broad proposal was to begin to use NHGRI sequencing capacity more directly and rapidly for the understanding of human disease. The working group expects that the medical impact of some of these projects could be high, but these disorders are rare. Therefore, the main benefit of identifying these genes would be to provide insight into the pathophysiology or biology of the disorders. Individual projects would require resequencing of perhaps 12,000 to 18,000 amplicons.

There are some challenges in identifying disorders that would be appropriate for this project. An initial set of specific disorders has been identified (See Project Descriptions below). These are not intended to be representative, but would rather serve as demonstration projects to determine whether, and how, a larger number of such projects would be pursued. Issues to be addressed include obtaining appropriate samples (with adequate existing informed consent or the ability to obtain new consent), interactions between sequencing centers and those with samples, understanding how many affected and control samples are needed, and providing appropriate results and analyses usable by the community.

At this stage, NHGRI has not solicited additional projects in this area.

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Project Descriptions

Lymphedema-Cholestasis Syndrome (LCS); Aagenaes Syndrome
Proposed by Laura Bull, University of California, San Francisco
Sequencing by Washington University in St. Louis

LCS is a rare autosomal recessive disorder that affects normal liver function and manifests as cholestasis (i.e. obstruction of bile flow) and lymphedema (i.e. excessive lymphatic fluid collecting in tissues causing swelling). Typically, affected infants have severe symptoms which may improve with age. In some cases, extensive liver disease requires a liver transplant. Later in life, affected individuals may have periodic cholestasis. Lymphedema associated with the disease can become severe, chronic, and progressive, impairing normal daily activities. Bull et al. mapped LCS to a ~6.6 cM region of 15q (OMIM #214900). They reported that known samples share the same haplotype defining the LCS region in a study of affected individuals and distant relatives (Bull et al. Am. J. Hum. Genet. 67:994-999, 2000). This project entails sequencing the 269-514 Kb candidate region within 8 individuals from different population groups and genotyping any variants identified in a control sample of about 76 Norwegian blood donors.

Joubert Syndrome (JBTS)
Proposed by Joseph Gleeson, University of California, San Diego
Sequencing by Broad Institute

JBTS is an autosomal recessive developmental brain disorder that affects ~1 in 10,000 individuals. It is characterized by underdevelopment or absence of the cerebellar vermis. Patients may exhibit lack of coordination in voluntary muscle movements (ataxia), rapid breathing (hyperpnea), decreased muscle tone (hypotonia), abnormal eye and tongue movements, mental retardation, polydactyly, cleft lip and palate, and tongue malformations (Keeler et al. Am. J. Hum. Genet. 73: 656-662, 2003). Research groups have identified 5 loci with evidence for linkage to JBTS. The investigator previously identified a gene on chromosome 6 with clear independent deleterious mutations associated with the disease using a candidate gene approach (OMIM # 608629) (Dixon-Salazar et al. Am. J. Hum. Genet. 75: 979-987, 2004). The plan for this project is to sequence JBTS1 (OMIM # 213300), within a 4.4 Mb candidate locus on chromosome 9 that includes ~107 genes in between 6 and 12 affected individuals.

Dominant Atrial Fibrillation (AF)
Proposed by Calum MacRae, Massachusetts General Hospital/Harvard University
Sequencing by National Institutes of Health Intramural Sequencing Center

Atrial fibrillation (AF) is the most common clinical arrhythmia and a major risk factor for heart failure or stroke. About 10% of the population age 70-80 is affected by AF. It can be a significant cause of morbitity and premature mortality. There is recent evidence from several studies that suggests three genetic loci are associated with AF. The proposing investigator described an autosomal dominant pattern of linkage between AF and a region on chromosome 6 (OMIM # 608988) based on a large kindred with 8 affected members (Ellinor et al. Circulation. 107: 2880-2883, 2003). This project will sequence regions within a 30 MB target interval that contains at least 87 genes in 12 affected family members and about 425 control samples.

Thoracic Aortic Aneurysms and Dissection (TAAD)
Proposed by Dianna Milewicz, University of Texas Health Science Center
Sequencing by National Institutes of Health Intramural Sequencing Center

Familial thoracic aortic aneurysms and dissection (TAAD) are caused by autosomal dominant single gene mutations that result in degeneration of the aortic media (medial necrosis) that leaves the ascending aorta prone to aneurysm and dissection (Guo et al. Circulation. 103: 2461-2468, 2001). Although linkage studies are difficult because the affected individual typically dies of the disease, the proposing investigator performed a multipoint linkage analysis that implicated a target region on chromosome 5 (OMIM # 607087) (Guo et al. Circulation 103:2461-2468, 2001). This project will sequence genes within a 16.5 Mb critical interval that contains ~87 genes with samples taken from autopsies and pathology slides of affected individuals.

Paroxysmal Kinesigenic Dyskinesia (PKD)
Proposed by Louis Ptacek, University of California, San Francisco
Sequencing by Washington University in St. Louis

Episodic disorders are some of the most common illnesses that affect human health. They include syndromes ranging from seizure disorders, migrane headaches, periodic paralyses, and episodic movement disorders. PKD is an episodic movement disorder that is induced by sudden changes in movement or orientation. It is characterized by involuntary muscle contractions resulting in repetitive distorted movement (dystonia), involuntary irregular jerky movements (chorea), writhing motions (athetosis), and flinging motions of the extremities (ballismus). Affected individuals may experience attacks at a frequency ranging from once per month to hundreds per day. Attacks can last from a few seconds to several hours (Swoboda et al. Neurology 55: 224-230, 2000). Severity and frequency of attacks typically decreases with age. An autosomal dominant form of PKD has been mapped to chromosome 16 (OMIM #602066) in Caucasian families (Szepetowski et al. Am. J. Hum. Genet. 61: 889-898, 1997). This project involves sequencing within a ~26 Mb candidate region that may include about 200 genes in ~3 affected individuals. Researchers will compare the results with controls from a Caucasian population.

Dominant Restrictive Cardiomyopathy
Proposed by Margaret Wallace, University of Florida
Sequencing by National Institutes of Health Intramural Sequencing Center

Dominant restrictive cardiomyopathy is an autosomal dominant disease in which a stiffening of the walls of the heart restricts normal blood flow to the chambers of the heart. Symptoms of the disease may include increased diastolic pressure and symptoms of heart failure. Investigators have associated desmin deposition in affected heart tissue without symptoms of skeletal myopathy with the disease (Zhang et al. Clin. Genet. 59: 248-256, 2001). The proposing investigator performed linkage analysis on 13 affected individuals and mapped the disease to a ~3 Mb candidate interval on chromosome 10 containing 25 genes (OMIM # 609578) (Zhang et al. Clin. Genet. 59: 248-256, 2001). In this project, the sequencing center will sequence regions within this candidate interval in a family of 13 affected individuals and 12 other family members to identify candidate gene mutations and follow-up sequencing in 2 affected and 2 unaffected individuals to screen candidate genes found in the large family.

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Approved Medical Sequencing Projects

Currently, there are no openings for new proposals in this area. However, NHGRI encourages investigators that are interested to contact program staff to discuss potential projects. Please send inquiries to the program contacts listed below.

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Program Contacts

Adam Felsenfeld, Ph.D.
Program Director

Jane Peterson, Ph.D.
Associate Director, Division of Extramural Research

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Last Reviewed: November 15, 2011