Low‐level germline mosaicism of a novel SMARCA2 missense variant: Expanding the phenotypic spectrum and mode of genetic transmission

Abstract

Background Nicolaides–Baraitser syndrome (NCBRS) is a severe neurodevelopmental disorder with multiple abnormalities. To date, all pathogenic variants in SMARCA2 causing NCBRS are de novo and most are missense variants located in the ATPase domain of SMARCA2 protein. Methods In this study, a familial trio whole‐exome sequencing was performed on the proband presenting with intellectual disability, early‐onset epilepsy, and autistic features. A novel missense variant c.553C>G (p.Gln185Glu) in SMARCA2 was identified, which is located in the QLQ domain. The same variant was subsequently also found in the mother's ongoing pregnancy. Samples from accessible tissues such as saliva and sperm other than blood were collected from the parents, and the detection of the target variant was performed by amplicon‐based deep sequencing. Results Low‐level mosaicism of the target variant c.553C>G (p.Gln185Glu) was detected in the father's sperm with allele fraction of 2.8% by amplicon‐based deep sequencing, which was not detected in either parents’ blood or saliva specimens. Heterozygosity of this variant was confirmed in the proband. Conclusion This is the first report of paternal germline mosaicism for a SMARCA2 disease‐causing variant. In addition, the missense variant c.553C>G (p.Gln185Glu) in the QLQ domain causes mainly neurological and developmental phenotypes with unremarkable characteristic facial features and limb abnormalities. Our findings expand the phenotypic spectrum and mode of genetic transmission associated with the SMARCA2 variants.

Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations

“…Among 10 families, two parental mosaicisms (Family 1 and Family 2) were detected, and no mosaicism (VAF<0.5 %) was detected in the remaining eight families. The VAF of SMARCA2 was 2.88% in the paternal sperm of Family 1 and was reported as a case report in our previous study 20. The VAF of SF3B4 was 2.5% in the paternal sperm of Family 2.…”

Living birth following preimplantation genetic testing for monogenic disorders to prevent low-level germline mosaicism related Nicolaides–Baraitser syndrome

“…Unfortunately, the same pathogenic variation was detected in amniocytes, and the woman underwent induced abortion again. The mosaicism of sperm carrying pathogenic allele was reported and verified as performed previously (Pan et al, 2021). The mosaicism is also presented in Figure 1.…”

“…In brief, the genomic regions which contain the missense SMARCA2 variant were targeted with the reference sequence (NG_032162.2, transcript: NM_003070.5) and then amplified specifically based on the primers (forward: 5-CCAACAGAG GTCCCTCACCT-3, reverse: 5-GCCTCGGGCCAGCATTTT AT-3). The PCR conditions were as previously described (Pan et al, 2021).…”

“…SNP linkage and chromosomal aneuploidy analysis were conducted based on SNP-array data. Sanger sequencing was also performed as previously described (Pan et al, 2021). Embryos diagnosed as unaffected were selected for transfer.…”

“…We have reported a case for being the first sperm mosaicism case of SMARCA2-related disease (Pan et al, 2021). The mosaicism seemed to be restricted to the paternal gonad because of undetectable pathogenic mutation in other somatic cells, including blood or buccal cells.…”