As for the data, I assume you've done Illumina sequencing. Your files are as follows:
FASTQ: short reads of the genome. CRAM: the reads aligned against a reference genome. VCF: small (probably <50bp, mostly SNPs) variants between your partner's genome and the reference, including your partner's genotypes (We are diploid, so there are two homologous copies of almost all loci in the genome, so you can have a variant that's in homozygosis---same alleles-- or heterozygosis--- different alleles.) The other files are index files that trivially describe the layout of these.
A substantial fraction of rare genetic disease (maybe 20%) relates to alleles found in the exome (the portion of the genome that directly codes for proteins in a 1:1 manner). You can look for rare variants that have significant effect on proteins. In most Illumina data sets, the significant majority of these will be genotyping or variant detection errors. Even ones that seem to lie in genes that are important for the etiology of your partner's phenotype are likely to be errors.
Other posters have linked to tools that might you predict the effect of given variants. You might also look at the variant effect predictor (VEP): https://grch37.ensembl.org/info/docs/tools/vep/index.html. This will classify the predicted effects of variants based on extremely detailed annotations of the genome. You can then find variants with high effect that are rare or nonexistent in the observed human population (using gnomad). Rare variants of highly deleterious functional effect with allele frequency >0% that your partner has in homozygosis may be candidates to follow up on. You will also want to look for variants that have AF=0% in the larger population and high effect size and your partner has in heterozygosis (they could be "dominant").
My impression is that most rare genetic disease is related to structural variation. This lies outside the scope of the short read resequencing which you've done. We don't even yet know the magnitude of this, because there are so few truly de novo assemblies of rare disease patients. The required technology has only come online in the past two years.
Between problems of observation of the genome and interpretation of the significance of variants, your job is not going to be easy. You will be confused by the signals you get, and probably follow many incorrect leads. Good luck.
Comments
A few notes to help you in this journey.
As for the data, I assume you've done Illumina sequencing. Your files are as follows:
FASTQ: short reads of the genome. CRAM: the reads aligned against a reference genome. VCF: small (probably <50bp, mostly SNPs) variants between your partner's genome and the reference, including your partner's genotypes (We are diploid, so there are two homologous copies of almost all loci in the genome, so you can have a variant that's in homozygosis---same alleles-- or heterozygosis--- different alleles.) The other files are index files that trivially describe the layout of these.
A substantial fraction of rare genetic disease (maybe 20%) relates to alleles found in the exome (the portion of the genome that directly codes for proteins in a 1:1 manner). You can look for rare variants that have significant effect on proteins. In most Illumina data sets, the significant majority of these will be genotyping or variant detection errors. Even ones that seem to lie in genes that are important for the etiology of your partner's phenotype are likely to be errors.
Other posters have linked to tools that might you predict the effect of given variants. You might also look at the variant effect predictor (VEP): https://grch37.ensembl.org/info/docs/tools/vep/index.html. This will classify the predicted effects of variants based on extremely detailed annotations of the genome. You can then find variants with high effect that are rare or nonexistent in the observed human population (using gnomad). Rare variants of highly deleterious functional effect with allele frequency >0% that your partner has in homozygosis may be candidates to follow up on. You will also want to look for variants that have AF=0% in the larger population and high effect size and your partner has in heterozygosis (they could be "dominant").
My impression is that most rare genetic disease is related to structural variation. This lies outside the scope of the short read resequencing which you've done. We don't even yet know the magnitude of this, because there are so few truly de novo assemblies of rare disease patients. The required technology has only come online in the past two years.
Between problems of observation of the genome and interpretation of the significance of variants, your job is not going to be easy. You will be confused by the signals you get, and probably follow many incorrect leads. Good luck.