The goal of this study is to identify and characterize novel non-coding and splicing variants that may contribute to genetic disorders. We will particularly focus on patients with a diagnosed genetic disorder that has inconclusive genetic findings.

To perform this study, we will use patient DNA and RNA that is isolated from blood samples. DNA will be sequenced (targeted capture and/or whole genome DNA sequencing (WGS)) to identify any non-coding single nucleotide variants (SNVs), smaller insertions/deletions (indels), or larger structural variants (SVs). RNA will be sequenced (RNA-seq) to identify genes that are expressed in a differential and/or allele-specific manner, which may indicate a functional non-coding or splicing variant. We will test the function of non-coding variants using high-throughput reporter assays and CRISPR based methodologies.

Inclusion criteria:

Subjects will have one or more of the following:

• Patients (probands) diagnosed with a genetic disease
• Patients (probands) with inconclusive genetic results
• Patients (probands) that have identical coding and/or splicing variants, but display highly diverse phenotypes
• Unaffected family members of probands

Exclusion Criteria: There are no exclusion criteria for this study.

Patients with diagnosed genetic disease and inconclusive genetic results and their unaffected family members

Data will be submitted to dbGaP, casual variants to ClinVar, aggregate rare phenotype and variant data to Geno2MP and other databases, candidate genes via a public list and linked to a node of the MatchMaker Exchange (MyGene2).

Data will be available 7-12 months after results are generated and will be available forever.