Carrier Screening · WES + PureTarget

Two layers of carrier risk, one clear answer.

Around 1 in 25 Indians carries beta-thalassaemia; carrier frequencies for SMA, G6PD deficiency, and many recessive disease alleles are substantial across communities. Yet most carrier panels are built on European allele frequencies. Our approach combines exome-wide carrier detection with long-read repeat expansion screening, and reports residual risk honestly — including where consanguinity changes the maths.

Plan Your Project → Learn the Basics
Exome-wide
carrier detection
PureTarget Carrier Panel
— 12 difficult genes
Consanguinity-aware
risk model
Pan-ethnic
, not panel-limited
About the Service

Carrier Screening at Nucleome Informatics

Carriers of a recessive or X-linked condition are usually healthy. When both partners carry a pathogenic variant in the same gene, each pregnancy has a 25% chance of being affected (50% for X-linked conditions with a carrier mother, modified by fetal sex).

1

Whole-exome carrier analysis

Exome-wide detection of pathogenic and likely-pathogenic variants in recessive and X-linked genes — not limited to a fixed list. Classified per ACMG/AMP guidelines.

2

PureTarget Carrier Panel

PacBio HiFi sequencing of 12 difficult genes that normally need Southern blots, MLPA or triplet-primed PCR — resolved in one long-read assay.

+
Optional upgrade

Repeat Expansion Panel

The full 38-locus PureTarget panel for couples with a neurological family history — repeat sizing, methylation and interruptions.

Why WES + PureTarget?

Pan-ethnic by designDetects the variants actually present in you, not just those on European-derived panel lists.
Repeats need long readsFMR1 premutations and FXN expansions are missed by exome and array methods.
Consanguinity-awareExome-wide detection plus homozygosity-aware interpretation captures family-specific alleles.

The 12 genes that defeat short reads

Pseudogenes, GC-rich tracts, duplications and repeats break routine NGS at these loci. Cas9 capture with HiFi reads resolves them:

Copy number & fusionsSMN1/2, CYP21A2
Large deletionsHBA1/2
Repeat size & methylationFMR1, FXN
Full exon sequenceF8, HBB, GBA, ARX, RPGR, TNXB, AFF2
F8Haemophilia A
FXNFriedreich ataxia
FMR1Fragile X disease
CYP21A2Congenital adrenal hyperplasia
TNXBClassical-like Ehlers–Danlos syndrome
HBA1/2Alpha thalassaemia
GBAGaucher disease
SMN1/2Spinal muscular atrophy
ARXEarly-infantile epileptic encephalopathy 1 / Partington syndrome
HBBSickle cell anaemia and beta thalassaemia
RPGRX-linked retinitis pigmentosa
AFF2Fragile X syndrome, FRAXE type

Most relevant to India’s common recessive risks

What you receive

Per-partner reportGene, variant, zygosity, ACMG class, disease and inheritance
Couple risk summaryShared carrier conditions with residual risk
Repeat resultsFMR1 CGG size and methylation; FXN GAA size
Consanguinity-adjustedIncluding identity-by-descent findings where relevant
Counselling supportPre- and post-test coordination via your clinician
Learning Path

From first principles to expert-level analysis

New here? Start with Foundations. Planning a study or reviewing results? Jump to Practitioner or Expert. Each level builds on the one before it, so you can read this page as a short course or dip in where you need to.

Start here if you are new to this service — six ideas that explain what it is and why it matters.

LEVEL 1

What is a carrier?

A person with one pathogenic copy of a recessive gene and one normal copy. Carriers are usually healthy but can have children affected if their partner carries a variant in the same gene.

LEVEL 1

Why screen before pregnancy?

Knowing carrier status before conception gives couples the full range of reproductive options — natural pregnancy with prenatal testing, preimplantation genetic testing (PGT), donor options, or simply informed monitoring.

LEVEL 1

Why two tests (WES + PureTarget)?

Exome sequencing finds "spelling mistakes" in genes but cannot read through long tandem repeats. Repeat expansion diseases (fragile X, Friedreich ataxia, myotonic dystrophy, etc.) need long-read sequencing. Together they cover both major classes of recessive risk.

LEVEL 1

What is fragile X premutation carrier screening?

FMR1 CGG repeats of 55–200 (premutation) cause fragile X-associated disorders and risk expansion to full mutation (>200) in offspring. This is invisible to exome sequencing and requires dedicated testing — included in our PureTarget layer.

LEVEL 1

Is this test for me if I have no family history?

Most children with recessive conditions are born to couples with no family history — that is precisely why population-level carrier screening is recommended (ACMG 2021 carrier screening guidelines).

LEVEL 1

What happens if we are both carriers?

The report quantifies the risk (typically 25% per pregnancy for autosomal recessive conditions). Reproductive options — PGT, prenatal diagnosis, donor gametes — are discussed with your genetic counsellor.

For scientists planning a project or reading a report: how each step works and how it can mislead.

LEVEL 2

The WES layer

Standard high-quality exome sequencing of each partner, followed by carrier-focused analysis: heterozygous pathogenic/likely-pathogenic variants in recessive and X-linked genes, classified per ACMG/AMP criteria.

LEVEL 2

The PureTarget layer

Cas9-captured, PCR-free HiFi sequencing using the PureTarget Carrier Panel — 12 recessive-disease genes including SMN1/2, HBB, HBA1/2, CYP21A2, GBA, F8, FMR1, and FXN — with copy-number and fusion-allele resolution. The full 38-locus repeat expansion panel is available as an upgrade for couples with neurological family history or research interest.

LEVEL 2

Detection limits — stated plainly

Exome-based carrier detection misses: exon-level deletions/duplications in many genes, variants in poorly captured regions, deep-intronic pathogenic variants, pseudogene-disrupted genes (SMN1, HBA1/2, GBA...), and phase (whether two variants sit on the same chromosome). Each report includes a gene-level detection-limit table and residual-risk estimates.

LEVEL 2

The SMN1 problem — and how we solve it

Spinal muscular atrophy carrier status depends on SMN1 copy number, which short-read exomes resolve poorly. The PureTarget Carrier Panel addresses this directly: Paraphase-based analysis in the PureTarget Carrier Pipeline (PTCP) resolves SMN1/2 copy number and gene–pseudogene fusion alleles from HiFi reads — no separate MLPA required.

LEVEL 2

Consanguinity-aware interpretation

For consanguineous couples, we examine homozygous regions and prioritise recessive variants within them; the residual-risk model accounts for the elevated probability of shared ancestral alleles.

LEVEL 2

Indian population context

Carrier frequencies are interpreted with gnomAD v4 and IndiGen genome data, and known Indian founder alleles (e.g. beta-thalassaemia IVS1-5 G>C, common in specific communities) are explicitly evaluated.

For study design: the decisions that determine whether the data answers your question.

LEVEL 3

Phase resolution for compound-heterozygote questions

Where an individual carries two variants in the same recessive gene, phase determines whether they are a carrier or affected. Exomes usually cannot resolve phase; targeted long-read or family-based approaches can — we flag every such case.

LEVEL 3

ACMG SF v3.3 secondary findings

Adult-onset and actionable findings (e.g. BRCA1/2, LDLR) can be reported per ACMG SF v3.3 (2025) with appropriate consent — optional, and clearly separated from carrier results.

LEVEL 3

Population-scale programmes

For community or cohort screening programmes, the 96-plex PureTarget workflow on Revio supports population-scale repeat expansion prevalence studies — relevant to Indian founder-allele mapping.

LEVEL 3

Residual risk calculation methodology

Residual risk = prior carrier probability × (1 − detection rate) for each gene, using population-specific carrier frequencies where available and detection rates derived from the exome's per-gene coverage and variant-type sensitivity. Methodology is documented in every report.

LEVEL 3

Quality and validation

Exome runs meet clinical-grade QC (coverage, uniformity thresholds agreed at intake); PureTarget follows PacBio's validated PTCP workflow. All classifications reference ClinVar submission history and literature.

LEVEL 3

Reporting standards

Reports follow ACMG/AMP variant classification, ACMG 2021 carrier screening recommendations, and include full methods, versions, and limitations.

Carrier
an individual heterozygous for a recessive disease allele, typically unaffected.
Residual risk
the remaining probability of being a carrier after a negative result, given the test's detection rate.
Premutation
an FMR1 CGG repeat of 55–200; unstable on transmission.
Consanguinity
union between related individuals; increases the probability of shared recessive alleles.
ACMG SF
American College of Medical Genetics secondary findings gene list (v3.3, 2025).
PGT
preimplantation genetic testing of embryos.
The Science

How it works, in two figures

The ACMG 2021 carrier screening practice guideline (Grody et al.) endorses pan-ethnic expanded carrier screening; population data (gnomAD v4; IndiGen) ground Indian carrier-frequency interpretation. See references below.

Figure 1 Two layers of risk. schematic
Fixed variant panels WES + PureTarget European-derived allele lists Repeat expansions invisible Panel-size ceiling Detects the variants you actually carry FMR1 / FXN repeat sizing included Consanguinity-aware risk model
Figure 1 | Two layers of risk. (Illustrative schematic, not sample data.)
Figure 2 Residual risk concept. schematic
Genetic counselling Blood sample (both partners) WES + PureTarget sequencing ACMG/AMP classification Couple-level risk summary Residual-risk report
Figure 2 | Residual risk concept. (Illustrative schematic, not sample data.)
Technology Highlights

Built for the questions you are asking

The platforms, pipelines and standards behind this service.

Exome-wide carrier detection

Heterozygous pathogenic variants across all clinically validated recessive and X-linked genes captured by the exome — hundreds of genes, without a panel-size ceiling.

PureTarget Carrier Panel

Cas9-captured HiFi sequencing of 12 recessive-disease genes (SMN1/2, F8, HBA1/2, HBB, CYP21A2, GBA, FMR1, FXN, ARX, RPGR, TNXB, AFF2) — with copy-number, fusion-allele, and methylation resolution at the loci short reads cannot call.

ACMG/AMP variant classification

Variants classified per ACMG/AMP 2015 criteria with ClinVar and population-frequency context (gnomAD v4, 807,162 individuals; IndiGen for Indian population context).

Pseudogene-aware calling

Genes notorious for false calls (e.g. HBA1/2, HBB, GBA, SMN1/2, CYP21A2) are covered by the PureTarget Carrier Panel with Paraphase-based copy-number and fusion-allele calling — and any gene where exome-based calling remains unreliable is flagged with detection-limit statements.

Residual risk mathematics

For genes where the exome cannot fully rule out carriage (e.g. deletion carriers, deep-intronic variants), we compute residual risk using population carrier frequencies — no false reassurance.

Couple-based reporting

Results are reported as couple-level risk: concordant carrier pairs, X-linked carrier status, and repeat expansion risks, with reproductive options discussed by the counselling team. ---

Scope Note

What this service does and does not cover

Scope note. Carrier screening assesses reproductive risk for recessive and X-linked conditions; it does not diagnose the screened individuals and does not detect all possible disease-causing variants. Detection limits are stated per gene in every report. Repeat expansion screening covers the loci included in the chosen PureTarget configuration. Clinical interpretation and reproductive decisions belong to the couple and their genetic counsellor; we provide the laboratory evidence base.---
Why Nucleome

Service highlights

What you can expect from our team in Hyderabad.

Pan-ethnic by construction

WES detects the variants you actually carry — no panel-list bias against Indian populations.

Repeat expansions and difficult genes included

PureTarget Carrier Panel (12 genes: SMN1/2, HBB, HBA1/2, CYP21A2, GBA, F8 and more) by default; full 38-locus repeat expansion panel available.

Honest detection limits

Gene-level limitations and residual risk stated in every report.

Consanguinity-aware analysis

Homozygosity-informed interpretation for related couples.

Couple-level reporting

Concordance summary and risk quantification, ready for counselling.

Clinical-grade QC

Exome and PureTarget workflows run to clinical reporting standards. ---

Questions

Frequently asked, in plain language

From the basics to the finer points of design and interpretation.

basicWho should consider carrier screening?
Any couple planning a pregnancy, especially with consanguinity, a family history of genetic disease, or community background with known founder alleles. Most affected children are born to couples with no prior family history.
basicHow is the test done?
A blood sample from each partner. Exome sequencing plus PureTarget repeat expansion sequencing are performed in our Hyderabad laboratory.
basicWhat if only one of us is a carrier?
For autosomal recessive conditions, the risk to children is minimal (children may be carriers). The report explains this per condition.
intermediateWhy can't exome sequencing detect fragile X carriers?
The FMR1 CGG repeat is too long and repetitive for exome reads to map through. PureTarget HiFi reads span the repeat directly and also report methylation.
intermediateWhat are the limitations of exome-based carrier screening?
Exon-level deletions/duplications, deep-intronic variants, pseudogene-affected genes, and variant phase are incompletely detected by exomes. Our design covers the worst of these genes (SMN1/2, HBA1/2, CYP21A2, GBA, F8 and eight others) with the PureTarget Carrier Panel, and every report includes a detection-limit table and residual-risk estimates for the remainder.
intermediateWhat is the PureTarget Carrier Panel?
A PacBio targeted panel that sequences 12 recessive-disease genes (F8, FXN, FMR1, CYP21A2, TNXB, HBA1/2, GBA, SMN1/2, ARX, HBB, RPGR, AFF2) with HiFi reads — resolving copy number, fusion alleles, deletions, repeat size, and methylation at loci that historically required Southern blots, MLPA, or triplet-primed PCR.
intermediateHow does consanguinity affect the results?
Consanguinity increases the chance that both partners carry the same ancestral allele. Our analysis examines shared homozygous regions and adjusts interpretation accordingly.
advancedHow is residual risk calculated?
Prior carrier probability (population frequency) multiplied by (1 − test detection rate) per gene, using per-gene coverage and variant-type sensitivity. The methodology is documented in the report.
advancedCan you resolve phase when both partners' exomes show two variants in one gene?
Standard exomes usually cannot. We flag such cases and offer targeted long-read or family-based phase resolution where needed.
advancedCan this be scaled to community screening programmes?
Yes — the 96-plex PureTarget workflow on Revio supports population-scale repeat expansion prevalence studies, and exome workflows scale for cohort carrier programmes.
advancedAre secondary findings reported?
Optionally, per ACMG SF v3.3 (2025), with explicit consent, and clearly separated from carrier results.
References

Key literature & resources

Selected sources behind the methods and reference values on this page. Figures labelled "schematic" or "illustrative" are generated for this page, not client data.

  1. Grody WW, et al. Carrier screening in the age of genomic medicine: a practice guideline of the American College of Medical Genetics and Genomics. Genetics in Medicine. 2021;23(12):2130–2139.
  2. Miller DT, et al. ACMG SF v3.3: updated points to consider for the reporting of secondary findings in clinical exome and genome sequencing. Genetics in Medicine. 2025;27(1):101254.
  3. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. Genetics in Medicine. 2015;17(5):405–424.
  4. Karczewski KJ, et al. The mutational constraint spectrum quantified from variation in 141,456 humans (gnomAD v2; current release v4 includes 807,162 individuals). Nature. 2020;581(7809):434–443.
  5. Naraindas J, et al. (IndiGen Consortium.) The IndiGen project: whole-genome sequencing of 1,029 Indians. Nucleic Acids Research. 2020;48(13):7245–7259.
  6. PacBio. PureTarget brochure: comprehensive characterization with PureTarget repeat expansion panel (PureTarget carrier panel: 12 genes; PTCP workflow; performance specifications). PacBio, REV08, 18 September 2025. https://www.pacb.com/wp-content/uploads/PureTarget-brochure.pdf
  7. Guha S, et al. Laboratory testing for preconception/prenatal carrier screening: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2024;26(7):101137.
  8. Nistala H, et al. — beta-thalassaemia carrier frequency in India: see also Colah R, et al. Community control of beta-thalassaemia in India. (Founder allele context, e.g. IVS1-5 G>C.)