Investigation of NRXN1 deletions: clinical and molecular characterization.

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.

Defining the impact of maternal cell contamination on the interpretation of prenatal microarray analysis.

PURPOSE: To understand the ability of microarray-based comparative genomic hybridization to detect copy-number variation in the presence of maternal cell contamination. METHODS: To simulate maternal cell contamination, normal female DNA was mixed at various levels with DNA carrying known copy-number variations. Mixtures were run on a whole-genome 135K oligonucleotide-based array. Data were analyzed with custom analysis software. RESULTS: The array and software design allowed detection of larger copy-number variations at higher levels of maternal cell contamination than smaller copy-number variations. The smallest duplications and deletions were obscured at 22-31% and 55-58% maternal cell contamination, respectively. With male fetal samples, the sex chromosome ratios started showing observable shifts at ~10% maternal cell contamination. CONCLUSION: As knowledge of the maternal cell contamination level aids in interpretation of array results, we recommend concurrent, independent maternal cell contamination studies for all fetal samples for accurate and timely results. With male fetal samples in our laboratory, interfering levels of maternal cell contamination can be excluded when the sex chromosome plots appear normal. Thus, reportable male microarray-based comparative genomic hybridization results may be occasionally achieved without maternal cell contamination studies. Because the effects of maternal cell contamination on microarray results are dependent on array platforms, experimental techniques, and software algorithms, each laboratory should perform its own analysis to determine acceptable levels of maternal cell contamination for its assays.

Referral patterns for microarray testing in prenatal diagnosis.

OBJECTIVE: To understand the prenatal referral patterns from the United States, Canada, and Israel for two whole-genome microarray platforms, each with a different resolution. METHOD: Physicians selected one of the two array designs to be performed on 1483 prenatal specimens for a 1-year period. We retrospectively examined detection rates, indications for study, and physician array selection. RESULTS: The lower resolution array (55 K) showed an ~32% decrease in the detection of results of unclear clinical significance while retaining the ability to detect all but one significant abnormality identified by the higher resolution array (135 K). A majority of samples were referred for abnormal ultrasound findings. Whereas the United States and Canada utilized the higher resolution array more often for this indication, Israel preferred the 55 K array. Referral patterns for parental anxiety were similar for the United States and Israel, with most cases being tested on the 55 K array. Few cases were referred for advanced maternal age or family history of a genetic condition from either Canada or Israel. CONCLUSION: Referral patterns varied between the countries and between indications for study. Understanding these differences will provide laboratories the critical information needed to develop array designs to meet the medical needs and patient desires for prenatal testing.