HUGE Lecture 12 10/08/2026

Translational Genomics Research

interdisciplinary field of study that turns basic scientific discoveries about the human genome into practical medical applications

Basis of clinical diagnosis

Clinical features

Basis of genetic diagnosis

Clinical genetic testing

What do Karyotypes identify

chromosome aberrations

What do chromosomal microarrays identify

large insertions/deletions

What does single gene testing (sanger) identify

single nucleotide changes and small insertions/deletions

What is the most comprehensive genetic test

Genome sequencing

Benefits of genome sequencing (number of genes)

comprehensive- sequence all genes in genome

Benefits of genome sequencing (mitochondria)

Detects mitochondrial variation

Benefits of genome sequencing (variant types)

Detects most variant types (CNVs, SNVs, indels, UPD)

Benefits of genome sequencing (analysis type)

Benefits of genome sequencing (analysis type)Conduct phenotype-independent analysis (a priori hypothesis not needed)

Benefits of genome sequencing (non-coding regions)

Sequence non-coding regions of the genome (assess regulatory variation)

Cons of genome sequencing (data)

Lots of data, requiring non-trivial computational and storage requirements

Cons of genome sequencing (analysis)

complex analysis

Cons of genome sequencing (cost)

More costly than other types of genetic testing (at least for now)

What are the outcomes comparing GS testing with usual-care testing

diagnostic rate and change in clinical management

Diagnostic rate of GS vs usual-care testing

GS diagnostic rate is higher than usual-care testing

What did GS testing result in for clinical management from the study about Acutely Ill Infants

GS testing resulted in change of clinical management for 21% of infants versus 10% who received usual-care testing

What was the most frequent change in clinical management with GS testing

subspecialty referral

Utility of comprehensive genetic testing (diagnosis, cost, odyssey, outcomes)

• increased genetic diagnosis

• cost-effective if ordered early in life

• prevention of diagnostic odyssey

• improved patient outcomes

What is GS testing considered by most insurance providers

GS testing is still considered investigational by most insurance providers

What was the point of SouthSeq

Evaluate safety and efficacy of return of genetics results by trained non-genetics NICU providers (clinical trial)

Where was SouthSeq conducted

NICUs across Southeast US

What was the enrollment of SouthSeq

Diverse enrollment, enriched for African Americans and patients from rural medically underserved areas

How long was the SouthSeq workflow

60 days

What was the SouthSeq workflow

1. Enroll family at SouthSeq clinical site (NICU)

2. Conduct genome sequencing of the proband only

3. Identify disease-causal genetic variation

4. Conduct sanger testing to confirm result and determine inheritance

5. Return SouthSeq findings to participant families

6. Results inform management and treatment

What does unaffected parent testing help identify

de novo or compound heterozygous disease-causal variation (causal inherited variation detected as well in cases of affected parent, incomplete penetrance, etc.)

Why are variants of unceratin significance returned in primary findings

because they could become pathogenic in the future

How many SouthSeq participants received a diagnostic or likely diagnostic result

30%

In how many unique genes was diagnostic variation detected and why is that significant

105 genes- significant because it shows you the diversity of disease phenotypes

Why did 55% of patients remain undiagnosed in SouthSeq even after long read sequencing

because we don’t understand certain parts of the genome and the variants in those regions

What are the caveats of comparing clinical genetic testing (CGT) and genome sequencing (GS)

• not controlled comparison since different hospitals have different resources

• different physicians order different genetic testing

• genetic resources vary across healthcare systems

What did SouthSeq find in terms of if GS missed any diagnostic findings found by CGT

No diagnostic findings from CGT were missed by GS

Why would CGT miss a diagnosis that GS detected

The clinical genetic test ordered was not appropriate to detect the disease-causal variant

What are the two strengths of GS over CGT

1. GS is more comprehensive and effective than the multiplicity of individual tests currently employed by providers

2. Requires no a priori hypothesis regarding relevant genes

What else can genomic testing detect

unexpected findings

Secondary findings (SFs)

Variants not related to the indication for testing, identified via a deliberate search, and medically relevant

Incidental findings (IFs)

Variants not related to the indication for testing, NOT identified via a deliberate search, and potentially medically relevant

How is a secondary finding defined

American College of Medical Genetics and Genomics (ACMG) published list of genes associated with clinically actionable conditions (deliberate search) and variants detected in these genes should be returned to patients/participants

Can patients/participants opt out of receiving ACMG SFs

yes

Are variants that are incidental findings on the ACMG secondary findings gene list

no

Are incidental findings associated with the indication for testing

no

What are the classifications of variants

Pathogenic, likely pathogenic, VUS, likely benign, benign

What types of variants can be returned as SFs/IFs

variants classified as pathogenic or likely pathogenic may be returned as SFs/IFs

What types of variants can NOT be returned as SFs/IFs

Variants of uncertain significance can not be returned as SFs/IFs

How do we detect/avoid SFs/IFs in genomic analysis

• Look for (or filter out) variants in ACMG SF genes

• Look for variants in genes associated w phenotypes that overlap patient clinical presentation (to avoid IFs)

How can SFs/IFs be detected other than genetic testing

non-sequence-based comprehensive testing modalities (chromosomal microarray, etc.)

Are secondary/incidental findings specific to genetic testing

NO

How many participants in SouthSeq received an incidental finding

1%