Phenotypic expansion illuminates multilocus pathogenic variation

Abstract

Purpose: Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene.

Methods: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes.

Results: Multilocus variation was identified in 31.6% (6/19) of families with phenotypic expansion and 2.3% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling.

Conclusion: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus.

Keywords: distinct/overlapping blended phenotypes; multilocus variation; neurodevelopmental disorder; personal genomes; phenotypic expansion of Mendelizing disease traits.

FIGURE 1.. Intrafamilial genotypic and phenotypic variability in HOU2293.

Pedigree structure of family HOU2293. Both affected siblings share a homozygous variant in MCPH1; however, the proband (BAB3640) has additional homozygous variants in ALG8 and CLN5, resulting in a more severe blended phenotype.

FIGURE 2.. Intrafamilial genotypic and phenotypic variability in HOU2337.

Pedigree structure of family HOU2337. Both affected siblings share a hemizygous variant in BCOR; the proband (BAB6228) has additional homozygous variants in MED17 and SPG7, resulting in a more severe phenotype due to the additional mutational burden. Cort, cortical; agCC, agenesis of the corpus callosum.

FIGURE 3.. Absence of heterozygosity mediates mutational burden at a single locus.

(A) Pedigree structure of family HOU1838 and segregation of the variants identified in AMPD2, AP4B1 and NOTCH2. (B) Images of proband (BAB4474) demonstrate narrow forehead, esotropia of the left eye, short nose and protruding tongue. (C) B-allele frequency calculated from exome variant data demonstrates several regions of AOH, marked by grey zones. Variants in AMPD2, AP4B1, and NOTCH2 are located within the same region of AOH. (D) Blended phenotypic features and associated syndromes are presented. ASD, atrial septal defect.

FIGURE 4.. Absence of heterozygosity mediates mutational burden at more than one locus.

(A) Pedigree structure of family HOU1857 and segregation of variants identified in C12orf65 and GPR126. (B) Both siblings had esotropia, progressive sensorimotor polyneuropathy with impaired walking and resultant contractures and deformities in their extremities. (C) B-allele frequency calculated from exome variant data demonstrates several regions of AOH within chromosome 6, marked by grey zones. Variants in GPR126 (red line) are located in a region of AOH. (D) B-allele frequency calculated from exome variant data demonstrates several regions of AOH within chromosome 12, marked by grey zones. Variants in C12ORF65 (red line) are located in a region of AOH.