Optical genome mapping identifies a homozygous deletion in the non-coding region of the SCN9A gene in individuals from the same family with congenital insensitivity to pain.

We report an index patient with complete insensitivity to pain and a history of painless fractures, joint hypermobility, and behavioral problems. The index patient descends from a family with notable cases among his maternal relatives, including his aunt and his mother's first cousin, both of whom suffer from congenital insensitivity to pain. The patient had normal results for prior genetic testing: fragile-X syndrome testing, chromosomal microarray analysis, and exome sequencing. Optical genome mapping detected a homozygous deletion affecting the noncoding 5' untranslated region (UTR) and the first non-coding exon of the SCN9A gene in all affected family members, compatible with recessive disease transmission. Pathogenic homozygous loss-of-function variants in the SCN9A gene are associated with impaired pain sensation in humans. Optical genome mapping can thus detect pathogenic structural variants in patients without molecular etiology by standard diagnostic procedures and is a more accessible diagnostic tool than short-read or long-read whole-genome sequencing.

Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy.

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.