Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the beta ig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.

Purpose:Cell-free DNA (cfDNA) testing for fetal aneuploidies was broadly implemented for common trisomies and sex-chromosome anomalies (SCAs). However, such an approach identifies only 75 to 85% of clinically relevant aneuploidies.Methods:We present a consecutive series of 6,388 cases, thus uncovering a broader array of aneuploidies, including the rare autosomal trisomies (RATs) and the maternally inherited deletion and duplication copy-number variations (CNVs), with complete and stratified follow-up by amniocentesis. Combined measurements of z-scores and the fetal fraction, in conjunction with fetal cfDNA enrichment, were used to stratify the likelihood of true and false results.Results:We obtained an incremental diagnostic yield of 50%; RATs and CNVs were found to be significant causes of fetal pathology. Scrutinizing z-scores and the fetal fraction made it possible to distinguish the sources of false-negative results; predict the likelihood of false-positive results for major trisomies and SCAs; classify maternal mosaic SCAs and CNVs, preventing false-positive results; and robustly identify maternally inherited CNVs and detect recurrent genomic disorders as a standardized function of the fetal fraction.Conclusion:With the clinical pertinence of this broader detection scheme confirmed, we offer recommendations for its implementation.Genet Med 19 2, 169–175.

What's already known about this topic? Non‐invasive genome‐wide screening of fetal aneuploidy by shotgun sequencing cell‐free DNA in maternal blood has been shown to effectively identify fetal trisomy 21, but the performance of screening for other aneuploidies is variable. What does this study add? Optimizing all individual steps in the procedure and performing rigorous quality control provides a test capable of replacing invasive testing for the major aneuploidies.

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