Synthetic cfDNA for Monogenic Disorder Screening: 51 Single-Gene Conditions
The next frontier in prenatal screening isn't chromosomes - it's single genes. As sequencing costs drop and analytical methods improve, NIPT is expanding into monogenic disorders: conditions caused by mutations in individual genes rather than whole chromosome abnormalities.
At Eabha Genomics, we generate synthetic cfDNA for 51 monogenic disorders, covering the conditions most relevant for prenatal screening - from common carrier conditions to rare de novo mutations.
The Monogenic Opportunity
Traditional NIPT detects aneuploidy by counting reads. Detecting a single nucleotide variant in cfDNA requires finding the needle in a haystack of fragmented DNA, where fetal DNA is mixed with maternal at ratios as low as 4%.
Companies like Natera, Myriad, and BGI are racing to add monogenic conditions to their panels. But validation is even harder than for aneuploidies - where do you find cfDNA samples with specific point mutations at known fetal fractions?
Conditions We Cover
Skeletal Dysplasias (De Novo Dominant)
| Condition | Gene | Our VAF | Prevalence |
|---|---|---|---|
| Achondroplasia | FGFR3 (G380R) | 0.070 | 1 in 15,000 |
| Thanatophoric dysplasia | FGFR3 (R248C) | 0.070 | 1 in 60,000 |
| Hypochondroplasia | FGFR3 (N540K) | 0.068 | 1 in 15,000 |
| Pfeiffer syndrome | FGFR1 (R661X) | 0.065 | 1 in 100,000 |
These FGFR3 mutations are de novo dominant - arising new in the fetus, detectable even when neither parent carries them. Prime targets for cfDNA screening.
Carrier Screening Conditions
| Condition | Gene | Our VAF | Prevalence |
|---|---|---|---|
| Cystic Fibrosis | CFTR (F508del) | 0.055 | 1 in 2,500 (EUR) |
| Sickle Cell Anemia | HBB (E6V) | 0.070 | 1 in 500 (AFR) |
| Spinal Muscular Atrophy | SMN1 | log2 -0.15 | 1 in 10,000 |
| Tay-Sachs Disease | HEXA | 0.100 | 1 in 3,500 (AJ) |
RASopathies
| Condition | Gene | Our VAF | Prevalence |
|---|---|---|---|
| Noonan syndrome | PTPN11 (N308D) | 0.075 | 1 in 2,500 |
| Costello syndrome | HRAS (G13D) | 0.072 | 1 in 300,000 |
| CFC syndrome | BRAF (Q257R) | 0.068 | 1 in 810,000 |
Neurodevelopmental
| Condition | Gene | Our VAF | Prevalence |
|---|---|---|---|
| Rett syndrome | MECP2 (R168X) | 0.085 | 1 in 10,000 |
| Dravet syndrome | SCN1A (F1846L) | 0.070 | 1 in 15,000 |
| Neurofibromatosis 1 | NF1 (R1947X) | 0.070 | 1 in 3,000 |
| Tuberous sclerosis | TSC2 (R1743Q) | 0.090 | 1 in 6,000 |
Connective Tissue & Craniofacial
| Condition | Gene | Our VAF | Prevalence |
|---|---|---|---|
| Marfan syndrome | FBN1 (C1039Y) | 0.065 | 1 in 5,000 |
| Osteogenesis imperfecta | COL1A1/COL1A2 | 0.070 | 1 in 15,000 |
| Treacher Collins | TCOF1 (K1060X) | 0.075 | 1 in 50,000 |
| CHARGE syndrome | CHD7 (R2178X) | 0.080 | 1 in 10,000 |
Treatable Metabolic Conditions
| Condition | Gene | Our VAF | Notes |
|---|---|---|---|
| Phenylketonuria | PAH (R408W) | 0.070 | Treatable (diet) |
| Pompe Disease | GAA | 0.065 | Treatable (ERT) |
| MCADD | ACADM (K329E) | 0.072 | Treatable (diet) |
| Biotinidase deficiency | BTD (R538C) | 0.070 | Treatable (biotin) |
Plus 30+ additional conditions including Duchenne MD, Hemophilia A, storage disorders, and more.
The Technical Challenge
Monogenic detection in cfDNA is hard because:
- Single nucleotide signal: Finding one variant among millions of fragments
- Low VAF: At 10% fetal fraction, a heterozygous fetal variant is present at 5% VAF
- PCR/sequencing errors: Error rates can approach the signal you're trying to detect
Our synthetic samples provide known variants at controlled variant allele frequencies (VAF), with configurable fetal fractions to test detection limits.
Why This Matters
Monogenic cfDNA screening is coming. Labs developing these assays need:
- Positive controls for rare mutations they'll never see clinically
- Validation data for regulatory submissions
- Sensitivity/specificity characterisation at different fetal fractions
Get Started
Our monogenic panel includes 51 conditions. Contact us to discuss your monogenic validation needs, or explore our full conditions database.