Prenatal Microarray Follow-Up Study

Prenatal Cytogenetic Diagnosis by Array-Based Copy Number Analysis: Follow-Up

The objectives of this multi-center collaborative study are to ascertain the frequency of specific copy number variants (CNVs) identified prenatally and to evaluate in detail through continued follow-up of the children the phenotypes associated with CNVs of known or uncertain clinical significance.

Study Overview

• Status: Completed
• Conditions: Genetic Diseases
• Intervention / Treatment: Other: 3-year follow-up

Detailed Description

Specifically the aims are as follows:

1. Determine the intellectual function of the children at age 3 years
2. Determine phenotypic characteristics other than intellectual function of the children at age 3 years
3. Determine the frequency of specific copy number variants discovered during routine prenatal diagnostic testing
4. Evaluate the educational, counseling and psychosocial implications of microarray testing as it is introduced as a standard prenatal diagnostic procedure.

• Study Type: Observational
• Enrollment (Actual): 184

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Center for Fetal Medicine
  • Maryland
    • Rockville, Maryland, United States, 20852
      • George Washington University Biostatistics Center
  • New York
    • Larchmont, New York, United States, 10538
      • Montefiore Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore LIJ
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
    • New York, New York, United States, 10075
      • OB/GYN Services PC
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Health System
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Women undergoing prenatal microarray testing during pregnancy.

Description

Eligibility Criteria for Enrollment into the 3 year Follow-up Cohort

Inclusion Criteria

1. Singleton or multi-fetal pregnancy with a prenatal invasive procedure resulting in a diagnosis by microarray analysis of a microdeletion/duplication less than 10 Mbs, either pathogenic or of uncertain significance, which is reported to the patient. This includes:

   • Infants diagnosed during prenatal diagnostic studies performed at the10 pre-specified prenatal diagnostic centers
   • Infants diagnosed by analysis of microarrays performed at the collaborating laboratories
   • Infants referred through the Prenatal Microarray Resource Center website
   • Children who will be at least 3 years of age by January of 2018, and who had a prenatally detected CNV <10 Mbs, either pathogenic or of uncertain significance OR

2. Children whose mothers were enrolled in the initial study (through July 2011) and who met inclusion criteria for follow-up in that phase, referred to as the "Index cohort". This includes:

   • CNVs of uncertain or known significance, some of which were not reported to the patient
   • Mosaic findings by karyotype and/or microarray alone.

Exclusion Criteria

1. Patient refusal to allow infant follow-up through the age of three
2. Patient not fluent in the English language
3. Patient under the age of 18
4. In surrogate pregnancies, the "rearing parents" are unavailable to give consent.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
3 year follow-up cohort; When the infants reach 24 months of age, the Study Follow-up Specialist will send all participants an age- appropriate Ages and Stages Questionnaire (ASQ) for completion. At as close to the age of 3 as possible, the following exams will be performed and are described below: The Vineland-II Adaptive Behavior Scale (VABS); Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV), or Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V, for siblings older than 7 years 7 months, when necessary); Children will also be photographed (for review by the study dysmorphologist)	Other: 3-year follow-up; When the infants reach 24 months of age, the Study Follow-up Specialist will send all participants an age- appropriate Ages and Stages Questionnaire (ASQ) for completion. At the age of 3, the following exams will be performed and are described below: The Vineland-II Adaptive Behavior Scale (VABS); Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV), or Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V, for siblings older than 7 years 7 months, when necessary); Children will also be photographed (for review by the study dysmorphologist)
Limited follow-up cohort; Women with children who will not reach the age of 2 years 6 months by the end of our study but have a prenatally diagnosed CNV will be recruited into the limited follow-up study. Each center will describe the study to eligible women and will verbally obtain their permission to be contacted by the Study Follow-up Specialist. The Study Follow-Up Specialist will contact the patient, explain the study, and obtain full written informed consent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Full Scale Intelligence Quotient (IQ) score	Full Scale IQ score from the Wechsler Preschool and Primary Scale of Intelligence IV or Wechsler Intelligence Scale for Children 5th edition	age 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of subjects with specific commonly occurring CNVs		detected prenatally
Percent of subjects with seizure disorders		age: up to 3 years
Percent of subjects with cerebral palsy		age: up to 3 years
Percent of subjects with dysmorphic features diagnosed by dysmorphologist		age 3 years
Percent of subjects with structural anomalies		age: up to 3 years
Verbal Comprehension composite score	Verbal Comprehension composite score from the Wechsler Preschool and Primary Scale of Intelligence IV	age: up to 3 years
Visual Spatial composite score	Visual Spatial composite score from the Wechsler Preschool and Primary Scale of Intelligence IV	age: up to 3 years
Working Memory composite score	Working Memory composite score from the Wechsler Preschool and Primary Scale of Intelligence IV	age: up to 3 years
Communication domain score	Communication domain score from the Vineland Adaptive Behavior Scale	age: up to 3 years
Daily Living Skills domain score	Daily Living Skills domain score from the Vineland Adaptive Behavior Scale	age: up to 3 years
Socialization domain score	Socialization domain score from the Vineland Adaptive Behavior Scale	age: up to 3 years
Motor Skills domain score	Motor Skills domain score from the Vineland Adaptive Behavior Scale	age: up to 3 years
Adaptive Behavior Composite score	Adaptive Behavior Composite score from the Vineland Adaptive Behavior Scale	age: up to 3 years
Age-adjusted Z scores for birth weight		birth
Age-adjusted Z scores for birth length		birth
Age-adjusted Z scores for head circumference		birth

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Human Genome Research Institute (NHGRI)

Publications and helpful links

General Publications

• Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/NEJMoa1203382.
• Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ. Women's experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med. 2013 Feb;15(2):139-45. doi: 10.1038/gim.2012.113. Epub 2012 Sep 6.
• Bernhardt BA, Kellom K, Barbarese A, Faucett WA, Wapner RJ. An exploration of genetic counselors' needs and experiences with prenatal chromosomal microarray testing. J Genet Couns. 2014 Dec;23(6):938-47. doi: 10.1007/s10897-014-9702-y. Epub 2014 Feb 27.

Helpful Links

• An online community providing information about prenatal chromosome microarray testing for both patients and providers with the goal of engaging families in research.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: June 10, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (Estimate): June 11, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2019
• Last Update Submitted That Met QC Criteria: March 21, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: genetic; prenatal; CNV; microarray; copy number variant; microdeletion; microduplication
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn
• Other Study ID Numbers: AAAL0100; 5U01HD055651 (U.S. NIH Grant/Contract)