Mutations in Genes Associated With Pentalogy of Cantrell

This study will collect blood, urine, and other tissue samples from patients with Pentalogy of Cantrell (POC) and other inherited diseases that may involve mutations in non-muscle myosin II-B heavy chain (MYH10). We will also collect samples from the relatives of affected individuals. POC is a very rare disorder in which patients have a combination of severe defects of the middle of the chest including the sternum (breastbone), diaphragm, heart, and abdominal wall. The defect are apparent before birth or at birth.

Participants may undergo a medical evaluation that could include a medical history routine blood tests, urine collection, chest x-ray, and electrocardiogram. In addition, blood, urine, saliva, buccal swab or tissue samples may be collected for protein and gene studies. The blood is drawn through a very small needle placed in an arm vein. Children may choose to have a buccal (cheek) sample taken instead of blood draw. Buccal samples can be collected by a cheek swab, in which a soft brush is rubbed on the inside lining of the mouth, or by having the child hold a tablespoon of mouthwash in his or her mouth for a full minute and then spit the mouthwash into a container. In addition, tissue samples may be collected from patients if they undergoing any surgical procedures that may be required as part of their general medical care.

Some of the cells obtained from patients or their relatives may be used to establish cell lines (a living tissue sample) that can be grown in the laboratory and used for experiments.

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Study Overview

• Status: Completed
• Conditions: Pentalogy of Cantrell

Detailed Description

The purpose of this multisite protocol is to collect protein, DNA, and RNA from blood, sputum, urine and/or tissue samples from patients with the diagnosis of Pentalogy of Cantrell (POC) or other related syndromes in order to identify possible causative genes. We will use whole exome/genome sequencing of probands, their parents, and, if available, the affected relatives of probands to look for any exomic/genomic mutations that could be associated with this syndrome. We have produced a mouse model with the mutant mice exhibiting problems with ventral wall closure including extrathoracic location of the heart (ectopia cordis), and defects in the abdominal wall with protrusion of the guts and liver. The mice, which have a single amino acid substitution in nonmuslce myosin II-B, have severe defects in both the heart and brain, and resemble humans born with POC, who manifest these same abnormalities.

• Study Type: Observational
• Enrollment (Actual): 59

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 98 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Primary clinical

Description

• INCLUSION CRITERIA:

  i. Index Cases

  1. Those patients who have a diagnosis of POC or other related syndromes (as defined under Study Design) confirmed by telephone discussion between the investigators and the patient s physician.
  2. Outside Institutions- All ages will be included
  3. At the Clinical Center - Those subjects that are greater than or equal to 2 years of age and older.

ii. Relatives of Index Cases

1. We may obtain samples from family members and/or relatives of those individuals who have a diagnosis of POC or other related syndrome confirmed by telephone discussion between the investigators and the referring physician with knowledge of the index case.
2. Outside Institutions - All ages will be included. At the Clinical Center - Those subjects that are greater than or equal to 2 years of age and older

iii. Fetal tissue:

1. We may obtain samples from patients with a fetal diagnosis of POC or other related syndrome with diagnosis confirmed by telephone discussion between the investigators and the referring physician.

2. Research use of the fetal tissue in accordance to NIH Division of Intramural Research (DIR) Program fetal tissue policy guidelines:

   1. No profits will be involved;
   2. NIH researchers will have no involvement in the termination of pregnancy, and
   3. The tissue must be obtained in accordance with Federal, state, and local law including those that govern basic research using human fetal tissue and research involving the transplantation of fetal tissue.

EXCLUSION CRITERIA:

Subjects seen at the Clinical Center - Those subjects that are less than or equal to 2 years of age and older.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Group 1; Index cases
Group 2; Relatives of Index Cases
Group 3; Fetal tissue

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify the gene(s) mutation (s) that causes Pentalogy of Cantrell	Identification of novel genes related to Pentalogy of Cantrell	ongoing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Since mutations in NM IIB may not be the sole cause of POC, we also intend to identify any other gene(s) mutation(s) that might be thecause of POC.	Identifying any other gene(s) mutation(s) that might be the cause of POC.	Ongoing
We may wish to procure tissues from patients with nonmuscle myosin IIA and IIC mutations in order to study the mechanism underlyingthese abnormalities.	Studying the mechanism underlying these abnormalities in procuredtissues from patients with nonmuscle myosin IIA and IIC mutations.	Ongoing

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Robert S Adelstein, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Ma X, Adelstein RS. In vivo studies on nonmuscle myosin II expression and function in heart development. Front Biosci (Landmark Ed). 2012 Jan 1;17(2):545-55. doi: 10.2741/3942.
• Ma X, Adelstein RS. The role of vertebrate nonmuscle Myosin II in development and human disease. Bioarchitecture. 2014;4(3):88-102. doi: 10.4161/bioa.29766. Epub 2014 Aug 6.
• Ma X, Adelstein RS. A point mutation in Myh10 causes major defects in heart development and body wall closure. Circ Cardiovasc Genet. 2014 Jun;7(3):257-65. doi: 10.1161/CIRCGENETICS.113.000455. Epub 2014 May 13. Erratum In: Circ Cardiovasc Genet. 2014 Aug;7(4):570.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2004
• Primary Completion (Actual): September 6, 2019
• Study Completion (Actual): September 6, 2019

Study Registration Dates

• First Submitted: May 25, 2004
• First Submitted That Met QC Criteria: May 24, 2004
• First Posted (Estimate): May 25, 2004

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 7, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Nonmuscle myosin IIB; Nonmuscle myosin IIA; Pentology of Cantrell; thoracoabdominal syndrdome; Nonmuscle Myosin IIC; Pentalogy of Cantrell; Non-muscle Myosin Heavy Chain Genes
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Nervous System Malformations; Abnormalities, Multiple; Neural Tube Defects; Pentalogy of Cantrell
• Other Study ID Numbers: 040202; 04-H-0202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No