Interpretation and reporting of large regions of homozygosity and suspected consanguinity/uniparental disomy, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG).

Genomic testing, including single-nucleotide variation (formerly single-nucleotide polymorphism)-based chromosomal microarray and exome and genome sequencing, can detect long regions of homozygosity (ROH) within the genome. Genomic testing can also detect possible uniparental disomy (UPD). Platforms that can detect ROH and possible UPD have matured since the initial American College of Medical Genetics and Genomics (ACMG) standard was published in 2013, and the detection of ROH and UPD by these platforms has shown utility in diagnosis of patients with genetic/genomic disorders. The presence of these segments, when distributed across multiple chromosomes, may indicate a familial relationship between the proband's parents. This technical standard describes the detection of possible consanguinity and UPD by genomic testing, as well as the factors confounding the inference of a specific parental relationship or UPD. Current bioethical and legal issues regarding detection and reporting of consanguinity are also discussed.

Prospective study of 22q11 deletion analysis in fetuses with excess nuchal translucency.

OBJECTIVE: The purpose of this study was to determine the frequency of 22q11 deletions (DiGeorge, velocardiofacial syndromes) in chromosomally normal fetuses with excess nuchal translucency. STUDY DESIGN: We evaluated chorionic villus sampling (CVS) samples submitted with an indication of excess nuchal translucency. If chromosome analysis was normal, permission was obtained to perform 22q11 microdeletion fluorescence in situ hybridization analysis. By Fisher exact test, the null hypothesis that there is no association between excess nuchal translucency and 22q11 deletions was tested. RESULTS: Among 239 CVS samples from fetuses with excess nuchal translucency, 93 (39%) were chromosomally abnormal. Of the remaining 146 specimens, 80 CVS samples were chromosomally normal, had documentation of nuchal translucency > 3.0 mm, and were included in the study at the referring obstetrician's request. None of the 80 fetuses with an increased nuchal translucency and normal karyotype demonstrated a 22q11 microdeletion. By Fisher exact test, the probability of 80 fetuses with excess nuchal translucency having no deletions of chromosome 22 was not significantly different than the expected rate of 0.18% (P value = 1). CONCLUSION: Routine 22q11 microdeletion analysis for fetuses with excess nuchal translucency is not indicated. Instead, we recommend storing an extra unbanded slide from the cultured CVS material to permit 22q11 FISH analysis should a cardiac malformation be identified later by fetal echocardiography.

The importance of investigating for uniparental disomy in prenatally identified balanced acrocentric rearrangements.

We report the finding of paternal isodisomy for chromosome 14 in a fetus found to have a der(14;14)(q10;q10) by amniocentesis. The pregnancy was complicated by severe polyhydramnios and elevated amniotic fluid alpha-fetoprotein (AFP). The infant showed features consistent with paternal uniparental disomy (UPD) including postnatal growth retardation, poor respiratory function, feeding difficulties, and evidence of hypertrophic cardiomyopathy. The present case, in addition to other reported cases of UPD involving balanced acrocentric rearrangements, supports testing for UPD in prenatally detected Robertsonian translocations and isochromosomes.