title: Discovery of variants unmasked by hemizygous deletions.
abstract: Array-based genome-wide segmental aneuploidy screening detects both de novo and inherited copy number variations (CNVs). In sporadic patients de novo CNVs are interpreted as potentially pathogenic. However, a deletion, transmitted from a healthy parent, may be pathogenic if it overlaps with a mutated second allele inherited from the other healthy parent. To detect such events, we performed multiplex enrichment and next-generation sequencing of the entire coding sequence of all genes within unique hemizygous deletion regions in 20 patients (1.53 Mb capture footprint). Out of the detected 703 non-synonymous single-nucleotide variants (SNVs), 8 represented variants being unmasked by a hemizygous deletion. Although evaluation of inheritance patterns, Grantham matrix scores, evolutionary conservation and bioinformatic predictions did not consistently indicate pathogenicity of these variants, no definitive conclusions can be drawn without functional validation. However, in one patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis and bilateral hearing loss, we discovered a second smaller deletion, inherited from the other healthy parent, resulting in loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene. Conceivably, inherited deletions may unmask rare pathogenic variants that may exert a phenotypic impact through a recessive mode of gene action.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Duran
authors.forename: Ruben
authors.initials: R
authors.lastname: Van't Slot
authors.forename: Ellen
authors.initials: E
authors.lastname: van Binsbergen
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Vogel
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Ploos van Amstel
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000483:Alleles; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods*; D017353:Gene Deletion; D018628:Gene Dosage; D015723:Gene Library; D005808:Genes, Recessive; D005820:Genetic Testing / Q000379:methods; D015894:Genome, Human; D006360:Heat-Shock Proteins / Q000235:genetics; D057898:Hemizygote; D006801:Humans; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000235:genetics; D010641:Phenotype; D012680:Sensitivity and Specificity
chemical_list: C113285:HSBP1 protein, human; D006360:Heat-Shock Proteins