Background The recurrent 1q21.1 CNV has been associated with considerable phenotypic variability ranging from normal to severe neurodevelopmental delay, noted even among members of the same family. The reason for this variability is unknown.

Objective We screened for mutations within the 1q21.1 CNV or genome wide that could explain the phenotypic variability among ten 1q21.1 carriers from 4 families.

Methods Whole exome sequencing (WES) was performed on 6 subjects with deletions, 4 subjects with duplications and their 4 unaffected family members using an Illumina HiSeq 2000 sequencing platform. Golden Helix SVS v8.1.5 was used for raw data analysis. We assessed deleterious (e.g. splicing, frameshift, stop gain or loss) de novo, recessive or compound heterozygous mutation in the most severely affected probands from three families, as well as rare and pathogenic mutations inherited from their 1q21.1 carrier parents. Eight bioinformatics tools were used to assess functional damage and conservation of variants. Their expression pattern and role in disease based on literature review were also considered.

Results We found no pathogenic mutations in the 1q21.1 CNV region in any of the subjects. One homozygous mutation and six pathogenic mutations inherited from the affected parent were selected for follow-up and involved genes MADD, ASIC3, ATF6, NOS1, PIK3C2G and ROMO1 and NAV2. It is of interest that the majority of these genes have a role in stress response to a variety of environmental conditions such (e.g. pH, oxygen levels) or in endoplasmatic reticulum stress response.

Conclusions Impaired stress response, due to pathogenic mutations, in carriers of 1q21.1 CNVs combined with more or less favourable environmental conditions during early development could contribute to their phenotypic variability and severity.