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Non-invasive prenatal testing (NIPT) is increasingly used in routine practice due to its high sensitivity and specificity in detecting fetal chromosomal anomalies. Several reports have highlighted that NIPT can diagnose previously unsuspected malignancy or benign copy number variation in the expectant mother. We report a case in which NIPT detected a duplication involving the 17p11.2-17p12 region with possible Potocki-Lupski syndrome in the fetus. However, on further questioning, the mother revealed that she had Charcot-Marie-Tooth neuropathy type IA (CMT1A) and thus using array CGH, we were able to confirm that the 17p duplication was maternal in origin, included only the typical CMT1A region and that the fetus had a normal chromosome complement. Although it may be rare for a mother to have a pathogenic chromosome duplication/deletion, with the expansion in scope of NIPT from classic trisomies to global chromosome coverage and monogenic conditions, more examples of fortuitous maternal diagnosis will certainly be forthcoming and this should be taken into account during pre-test genetic counseling.

Non-invasive prenatal testing (NIPT) is increasingly used in routine practice due to its high sensitivity and specificity in detecting fetal chromosomal anomalies. Several reports have highlighted that NIPT can diagnose previously unsuspected malignancy or benign copy number variation in the expectant mother. We report a case in which NIPT detected a duplication involving the 17p11.2-17p12 region with possible Potocki-Lupski syndrome in the fetus. However, on further questioning, the mother revealed that she had Charcot-Marie-Tooth neuropathy type IA (CMT1A) and thus using array CGH, we were able to confirm that the 17p duplication was maternal in origin, included only the typical CMT1A region and that the fetus had a normal chromosome complement. Although it may be rare for a mother to have a pathogenic chromosome duplication/deletion, with the expansion in scope of NIPT from classic trisomies to global chromosome coverage and monogenic conditions, more examples of fortuitous maternal diagnosis will certainly be forthcoming and this should be taken into account during pre-test genetic counseling.

To assess the potential of detecting copy number variations (CNVs) directly from exome sequencing (ES) data in diagnostic settings, we developed a CNV-detection pipeline based on ExomeDepth software and applied it to ES data of 450 individuals. Initially, only CNVs affecting genes in the requested diagnostic gene panels were scored and tested against arrayCGH results. Pathogenic CNVs were detected in 18 individuals. Most detected CNVs were larger than 400 kb (11/18), but three individuals had small CNVs impacting one or a few exons only and were thus not detectable by arrayCGH. Conversely, two pathogenic CNVs were initially missed, as they impacted genes not included in the original gene panel analysed, and a third one was missed as it was in a poorly covered region. The overall combined diagnostic rate (SNVs + CNVs) in our cohort was 36%, with wide differences between clinical domains. We conclude that (1) the ES-based CNV pipeline detects efficiently large and small pathogenic CNVs, (2) the detection of CNV relies on uniformity of sequencing and good coverage, and (3) in patients who remain unsolved by the gene panel analysis, CNV analysis should be extended to all captured genes, as diagnostically relevant CNVs may occur everywhere in the genome.

Since the beginning of population screening for CF carriers, it has become apparent that complex CFTR alleles are not uncommon. Deciphering their impact in disease pathogenesis remains a challenge for both clinicians and researchers. We report the observation of a new complex allele p.[R74W+R1070W+D1270N] found in trans with a type 1 mutation and associated with clinical diagnosis of cystic fibrosis in a one year-old Moroccan patient. This case underlines the difficulties in counseling patients with uncommon mutations and the necessity of functional studies to evaluate the structure–function relationships, since the association of several variations in cis can dramatically alter CFTR function.