Genetic Testing Identified Tay-Sachs Disease Despite Normal Prenatal Ultrasound

Overview

• A Redcliffe Labs-led case report, published in the Iranian Journal of Neonatology, describes the antenatal diagnosis of Tay-Sachs disease despite no major abnormalities being detected on routine prenatal ultrasound.
• The case involved a 30-year-old woman at 19 weeks of pregnancy with a significant family history of unexplained childhood illness and deaths, including two previous daughters who died in childhood and another daughter with seizures and global developmental delay.
• Given the history of consanguinity and suspected inherited disease, clinicians pursued genomic evaluation despite the reassuring prenatal ultrasound.
• Whole-exome sequencing (WES) of both parents followed by Sanger sequencing of the fetus identified disease-causing variants in the HEXA gene, confirming the diagnosis of Tay-Sachs disease.
• The case highlights how detailed family history, genetic counseling, and advanced genomic testing can complement routine prenatal investigations when an inherited disorder is suspected.

The Research: When Ultrasound Was Reassuring, But Family History Was Not

Prenatal ultrasound is an essential part of pregnancy care. It helps clinicians monitor fetal development and identify many structural abnormalities.

But not every genetic or metabolic disorder produces visible structural changes on ultrasound, especially at the time of the scan.

A recently published case report by researchers including Dr. Himani Pandey of Redcliffe Labs illustrates this diagnostic challenge.

The study, titled “A Rare Case of Antenatally Diagnosed Tay-Sachs Disease,” was published in Volume 17, Issue 3 of the Iranian Journal of Neonatology in 2026. The report describes a 30-year-old woman who was 19 weeks pregnant and had a significant history of unexplained childhood illness and deaths in her family.

Despite the concerning family history, the prenatal ultrasound did not reveal major abnormalities.

The clinical history, however, raised a different question:

Could there be an inherited disorder that routine imaging was not able to detect?

That question led to genomic testing.

The Case: A Significant Family History

The patient was 30 years old and 19 weeks pregnant.

Her previous pregnancy history was particularly concerning.

Two of her daughters had died at 11 months and five years of age, respectively, with suspected metabolic or neurodegenerative disorders.

Another daughter had developed seizures and global developmental delay, along with facial dysmorphism and macrocephaly.

The presence of multiple affected children, together with a history of consanguinity, increased the clinical suspicion of an inherited genetic condition.

Yet the current pregnancy did not initially provide an obvious answer through routine prenatal imaging.

The ultrasound did not show major abnormalities.

This created an important diagnostic gap:

The pregnancy appeared structurally reassuring, but the family history suggested that something more could be present.

Why Did the Family History Matter?

Family history can sometimes provide one of the earliest clues to an inherited disorder.

Patterns such as:

• Unexplained childhood deaths
• Developmental delay
• Seizures
• Progressive neurological deterioration
• Recurrent infant or childhood illness
• Recurrent pregnancy or infant loss
• Multiple affected siblings
• Consanguinity
• A previously suspected but undiagnosed genetic or metabolic condition

may suggest that an underlying inherited disorder deserves further investigation.

In this case, the pattern across previous children was a critical part of the clinical picture.

The absence of major ultrasound abnormalities did not eliminate the possibility of a genetic disorder.

Instead, the family history prompted clinicians to look beyond imaging.

What Did Genetic Testing Reveal?

Given the clinical and family history, whole-exome sequencing (WES) was performed for both parents.

This was followed by Sanger sequencing of the fetus to investigate the suspected familial genetic finding.

The testing identified disease-causing variants in the HEXA gene associated with Tay-Sachs disease.

The diagnosis demonstrated the value of combining different sources of clinical information:

Family History → Clinical Suspicion → Genomic Testing → Variant Identification → Diagnosis

The case therefore demonstrates how genomic testing can provide answers when routine prenatal investigations alone may not explain the underlying risk.

What Is Tay-Sachs Disease?

Tay-Sachs disease is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the HEXA gene.

The HEXA gene provides instructions for the alpha subunit of beta-hexosaminidase A (Hex A), a lysosomal enzyme.

When disease-causing variants significantly impair Hex A activity, certain fatty substances, including GM2 ganglioside, accumulate within cells, particularly in the nervous system.

This progressive accumulation can cause severe neurological damage.

The classic infantile form of Tay-Sachs disease is associated with progressive neurological deterioration beginning in early childhood and can be life-threatening.

How Is Tay-Sachs Disease Inherited?

Tay-Sachs disease follows an autosomal recessive inheritance pattern.

This means an affected child generally inherits a disease-causing variant in the relevant gene from both biological parents.

Parents who each carry one disease-causing variant may not have the disease themselves but can pass the variant to their children.

This is why identifying a genetic diagnosis in one family can have implications that extend beyond a single pregnancy.

It can provide information relevant to:

• The current pregnancy
• Future pregnancies
• Testing of family members where appropriate
• Carrier assessment
• Genetic counselling
• Reproductive decision-making

Why Didn't the Prenatal Ultrasound Detect It?

This case does not suggest that prenatal ultrasound is ineffective.

Rather, it highlights that different diagnostic tools answer different clinical questions.

Ultrasound is primarily used to evaluate fetal anatomy, growth and other observable features.

Some genetic and metabolic disorders may not cause detectable structural abnormalities at the stage when an ultrasound is performed.

Therefore, a normal or reassuring ultrasound does not necessarily exclude every genetic condition.

When clinical or family history raises suspicion of an inherited disorder, genetic testing can provide information that imaging alone cannot.

Why Was Whole-Exome Sequencing Important?

Whole-exome sequencing examines the protein-coding regions of a person's genome, known as exons.

These regions contain many genes in which disease-causing variants can occur.

In a clinically complex case where the specific genetic condition is not known in advance, WES can help identify variants across many genes simultaneously.

In this case, the combination of parental WES and fetal Sanger sequencing enabled the investigators to identify the genetic basis associated with Tay-Sachs disease.

This illustrates one of the important applications of genomic medicine:

When the clinical picture suggests an inherited disorder but the diagnosis is unclear, broad genomic testing can help identify the underlying genetic cause.

Why Was Sanger Sequencing Used?

Sanger sequencing is a highly established DNA sequencing method that can be used to examine a specific genetic region.

Once a relevant familial variant has been identified, targeted sequencing can be used to confirm whether that variant is present in an individual.

In this case, Sanger sequencing of the fetus followed the parental whole-exome analysis, providing targeted investigation of the suspected genetic finding.

This demonstrates how different genomic technologies can work together rather than functioning as alternatives to one another.

Why Does This Case Matter?

The significance of this report extends beyond Tay-Sachs disease.

It demonstrates a broader principle in genetic medicine:

A normal imaging result does not always answer a genetic question.

When the clinical history suggests a possible inherited disorder, the diagnostic approach may need to combine:

Family History + Clinical Assessment + Genetic Counselling + Genomic Testing

This integrated approach can be particularly important in families with previous unexplained childhood deaths, developmental disorders, seizures or recurrent adverse pregnancy outcomes.

The India Context: What Do We Know About Tay-Sachs Disease?

Tay-Sachs disease is rare, but research from India has demonstrated considerable genetic diversity among affected families.

A multicentric Indian study of 34 enzymatically confirmed Tay-Sachs families identified 25 HEXA variants among affected patients and carrier couples. The study reported that 67% of the genotypes observed were novel, highlighting substantial molecular heterogeneity among Indian patients.

Earlier Indian research has similarly documented multiple novel HEXA variants and highlighted the need to better understand the molecular spectrum of Tay-Sachs disease in the Indian population.

More recently, a national Indian lysosomal-storage-disorder biobank study reported 62 Tay-Sachs cases within a cohort of 530 patients representing 27 lysosomal storage disorders, further demonstrating the importance of building clinical and genomic knowledge around rare diseases in India.

Together, these studies point to an important reality: the genetic landscape of rare inherited disorders in India can be highly diverse, making accurate molecular diagnosis particularly valuable.

What Does This Mean for Families With a History of Rare Disease?

A family history of unexplained illness does not automatically mean that a genetic disorder is present.

However, certain patterns can justify a conversation with a clinician or genetic counsellor.

These may include:

• Multiple children in the same family with similar unexplained illnesses
• Unexplained childhood deaths
• Developmental delay or regression
• Seizures without a clear cause
• Suspected metabolic or neurodegenerative disorders
• Recurrent pregnancy or infant loss
• Known inherited disease in the family
• Consanguineous marriage

In such situations, a detailed three-generation family history can help clinicians determine whether genetic evaluation may be appropriate.

Expert Perspective

Dr. Himani Pandey, Lab Head – Genomics, Redcliffe Labs, and corresponding author of the study, highlights the importance of looking beyond routine investigations when the clinical history suggests a possible inherited disorder.

“Many rare inherited disorders may not be detectable through routine prenatal ultrasound alone. A detailed family history can provide important clinical clues, while advanced genomic testing can help identify the underlying genetic cause.”

The case demonstrates why genetic diagnosis is not simply about identifying a gene variant.

It is about connecting the clinical history, family pattern and molecular finding to arrive at a more complete understanding of the condition.

What Does This Mean for Future Pregnancies?

Once a disease-causing familial variant has been identified, it can provide valuable information for future reproductive planning.

Depending on the specific diagnosis and family circumstances, targeted genetic testing and genetic counselling may help clinicians assess the risk in subsequent pregnancies.

The appropriate approach is individualised and should be discussed with qualified genetic and reproductive-health professionals.

The key advantage is having specific genetic information available when making those decisions, rather than trying to determine risk based only on clinical history or imaging.

Redcliffe Labs’ Contribution to Genomic Research

The case report reflects Redcliffe Labs' broader work in advancing genomic diagnostics and contributing clinical evidence in rare and inherited disorders.

Redcliffe Labs' genomic capabilities include:

• Whole-Exome Sequencing
• Clinical Exome Sequencing
• Targeted genetic testing
• Sanger sequencing
• Chromosomal microarray
• Prenatal genetic investigations

These capabilities support the investigation of rare diseases, inherited conditions and reproductive-health concerns.

For Redcliffe Labs, research and publication are an important part of strengthening the evidence base around advanced diagnostics and contributing to a deeper understanding of rare genetic conditions in India.

Why Publishing Clinical Research Matters

A rare case can provide more than an answer for one family.

When documented and published, it can contribute to the wider medical understanding of how a condition presents, how it can be investigated and where conventional diagnostic approaches may have limitations.

For rare inherited disorders, where individual clinicians may encounter only a small number of cases, sharing clinical and genomic findings can help build a larger body of evidence.

This is particularly relevant in genetically diverse populations such as India, where the spectrum of disease-causing variants may differ across communities and regions.

About the Publication

Study: A Rare Case of Antenatally Diagnosed Tay-Sachs Disease
Journal: Iranian Journal of Neonatology
Volume: 17
Issue: 3
Year: 2026
Pages: 55–58
Authors: Sonal Gupta, Devi Lal, Juhi Bhalotia, O.P. Gupta and Himani Pandey.

The publication documents an antenatally diagnosed case of Tay-Sachs disease and describes the role of parental whole-exome sequencing and fetal Sanger sequencing in establishing the diagnosis.

The Key Takeaway

A reassuring prenatal ultrasound can provide important information about fetal development—but it cannot rule out every inherited genetic disorder.

This Redcliffe Labs case demonstrates how a detailed family history raised suspicion of an inherited condition despite the absence of major abnormalities on routine prenatal imaging.

The subsequent use of whole-exome sequencing and Sanger sequencing identified disease-causing HEXA variants associated with Tay-Sachs disease.

The larger lesson is about bringing different forms of evidence together:

Family history can raise the question.
Genetic counselling can guide the investigation.
Genomic testing can help find the answer.

For families facing unexplained childhood illness, developmental disorders, recurrent adverse pregnancy outcomes or suspected inherited disease, that combination can provide important information for more informed clinical and reproductive decision-making.

About Redcliffe Labs

Redcliffe Labs is an impact-driven diagnostic healthcare network working to redefine healthcare access across India and add Healthy Years to Lives. The organisation operates across 220+ cities through 80+ owned advanced laboratories and a network covering 4,000+ pincodes, offering 3,600+ diagnostic tests supported by clinical expertise and technology.

With capabilities spanning pathology, radiology and advanced genomics, Redcliffe Labs is expanding its role in preventive and precision diagnostics while contributing to clinical research focused on rare, inherited and reproductive-health conditions.

Through research, evidence generation and advanced diagnostic capabilities, Redcliffe Labs aims to contribute to a deeper understanding of disease and support more informed clinical decision-making across India.