ALMS1 in Sphynx Cats — What You Really Need to Know

Introduction

The ALMS1 variant has been studied in Sphynx cats since 2021. Since then, several independent research groups have investigated its possible role in hypertrophic cardiomyopathy (HCM). Some studies reported an association, while others were unable to reproduce it.

This article brings together all of the major published studies in one place. It explains what each study investigated, what the researchers found, what the limitations were, and how scientific understanding has evolved over time.

The aim is not to tell you what decision to make. It is to help you understand the evidence, so you can make an informed one.

One phrase you will see repeatedly

When researchers say a finding is “statistically significant”, they mean the result is unlikely to be a coincidence. When they say a result was not significant, they are not saying nothing is there — they are saying that, with the number of animals studied, they could not show that the difference was real rather than something that happened by chance.

That distinction runs through everything below.

Why was ALMS1 investigated?

ALMS1 attracted researchers’ attention because it already had a recognised role in human medicine. Pathogenic variants in this gene cause Alström syndrome, a rare inherited disorder that can affect several organs, including the heart.

Studies in humans have shown that ALMS1 is involved in how heart muscle cells develop, stop dividing after birth and maintain normal heart function. People with Alström syndrome may develop cardiomyopathy, most commonly dilated cardiomyopathy (DCM) in infancy or restrictive cardiomyopathy (RCM) later in life.

This made ALMS1 a biologically plausible candidate gene to investigate in Sphynx cats with HCM. However, biological plausibility is not the same as proof. Every scientific hypothesis must be tested, and that is exactly what the following studies set out to do.

Research Timeline

2021 – Meurs et al. The study that started the ALMS1 story

In February 2021, Professor Kathryn Meurs and colleagues from North Carolina State University published the first study linking the ALMS1 c.7384G>C variant to hypertrophic cardiomyopathy (HCM) in Sphynx cats.

This was the first study to report an association between the ALMS1 variant and HCM in Sphynx cats.

What did the researchers do?

The team studied 71 Sphynx cats diagnosed with HCM and compared them with 214 cats from 14 other breeds that had no known heart disease. They also examined heart tissue from affected cats to investigate how the variant might affect the heart.

What did they find?

The ALMS1 variant was found in 62 of the 71 affected Sphynx cats, compared with only 2 of 214 cats from other breeds. Based on these numbers, the researchers estimated that around three quarters of cats carrying the variant would be expected to develop the disease, and that carriers appeared many times more likely to be affected than non-carriers. These were estimates drawn from this particular group of cats, not from the breed as a whole. (Reported penetrance 77%; relative risk 13.6.)

However, one important finding is often overlooked.

Nine cats with HCM did not carry the ALMS1 variant at all.

The authors therefore concluded that ALMS1 was not the only genetic factor involved and that other causes of HCM were likely to exist in Sphynx cats.

Why wasn’t this the final answer?

The researchers also explained an important limitation of their study.

The control group consisted of cats from other breeds, not healthy Sphynx cats. Because HCM can develop later in life, they explained that it was difficult to identify Sphynx cats that could confidently be considered unaffected.

For this reason, the study identified a strong association, but it could not determine whether the variant was truly disease-causing or simply a genetic variant commonly found in the breed.

Why does this study still matter today?

This study changed the direction of feline cardiology research. It identified ALMS1 as a promising candidate gene and led to a series of independent studies designed to answer the same question in different Sphynx populations.

2023 – Akiyama et al. Looking beyond the Sphynx breed

After the 2021 study, one important question remained unanswered: Was the ALMS1 variant unique to Sphynx cats, or could it also be found in other breeds?

To answer that question, researchers in Japan examined cats from a wide range of breeds.

What did the researchers do?

They looked for the same ALMS1 variant in cats from different breeds, including Scottish Fold, Munchkin, American Shorthair, Exotic Shorthair and Minuet. They also compared 18 Scottish Fold cats with HCM to 132 Scottish Fold cats from the general population.

What did they find?

The ALMS1 variant was not unique to Sphynx cats. It was found in several other breeds where it had not previously been reported. The researchers also compared Scottish Fold cats with and without HCM. The difference between the two groups was not large enough to be considered statistically meaningful — in other words, it could have arisen by chance.

Why was this important?

This study changed how the original 2021 findings should be interpreted. The control group used by Meurs included cats from 14 other breeds, but none of the breeds later shown to commonly carry the ALMS1 variant were included. In other words, the fact that the variant was rare in the original control group may have reflected which breeds were selected, rather than proving that the variant was rare outside the Sphynx breed.

Did this prove ALMS1 was harmless?

No.

The study did not show that ALMS1 is harmless or irrelevant. It simply showed that the variant is found in more breeds than previously thought, and that this particular study did not find a significant association with HCM in Scottish Fold cats. The authors concluded that the variant should be investigated in larger populations and across different breeds.

2023 – Turba et al. - Why the test itself also needed checking

While researchers were still trying to understand what ALMS1 might mean, an Italian team found a different problem:

Could the DNA test sometimes give the wrong result?

What did the researchers do?

The team tested 136 Sphynx cats for the ALMS1 variant.

In one family, the result did not match the expected inheritance from parent to kitten. That suggested the test had failed to detect one copy of the gene correctly.

What did they find?

The researchers discovered five previously unknown DNA changes close to the ALMS1 variant. Three of them were located exactly where the original test attached to the DNA. Because of this, one copy could be missed—a problem called allele drop-out. The team redesigned the test to avoid those nearby changes.

Why was this important?

It showed that before interpreting an ALMS1 result, we first need to know that the test identified the result correctly.

This study did not prove that every ALMS1 test is unreliable. It showed that the design of the test matters and that laboratories need to account for the published allele drop-out problem.

The study also found that the ALMS1 variant was very common in the Italian Sphynx population, with a frequency above 50%. The authors said more heart examinations and follow-up were still needed to compare the variant with actual HCM diagnoses.

2024 – Boeykens et al. - The study that formally classified ALMS1

By 2024, several feline DNA variants were being sold or discussed as tests for HCM. Researchers therefore asked a basic question: How strong is the evidence behind each one?

What did the researchers do?

An international team of feline genetics and cardiology experts reviewed six published variants previously linked with HCM in different cat breeds.

They used a system called ACMG, developed in human genetics and now applied in animals too. It does not ask “does this variant cause disease?” — it asks “how strong is the evidence either way?”, and grades the variant accordingly.

The system weighs evidence such as:

• how common the variant is;

• whether it appears more often in affected cats;

• whether it follows the disease through families;

• and whether laboratory studies support a harmful effect.

What did they find?

Some feline HCM variants had enough evidence to receive a stronger classification. ALMS1 c.7384G>C did not.

It was classified as a: Variant of Uncertain Significance — VUS

This means there was not enough evidence to classify it as disease-causing, but there was also not enough evidence to classify it as harmless.

Why was this important?

This gave ALMS1 a clear scientific status — VUS.

Did VUS mean “irrelevant”?

No. VUS means uncertain, not irrelevant. It tells us that the available evidence cannot yet answer the question reliably in either direction and it is not a permanent classification.

As new evidence becomes available, a Variant of Uncertain Significance may be reclassified as:

• Pathogenic – proven to cause disease.

• Likely pathogenic – strong evidence suggests it causes disease.

• Likely benign – evidence suggests it is unlikely to cause disease.

• Benign – strong evidence shows it does not cause disease.

The purpose of a VUS classification is not to provide a final answer. It reflects the current state of scientific knowledge and may change as new research becomes available.

2024 – Seo et al. - Following the same cats over time

Most earlier studies compared one group of cats with another. The New Zealand study took a different approach. Instead of comparing different cats, the researchers followed the same Sphynx cats over time to see which ones developed HCM.

What did the researchers do?

The team examined 55 apparently healthy Sphynx cats using echocardiography (heart ultrasound). Around two years later, 42 of those cats were examined again to see whether their heart scans had changed. Every cat was also tested for the ALMS1 variant.

What did they find?

The ALMS1 variant was very common in the study population and was found in 70.9% of the cats. However, the researchers found no significant association between the variant and HCM.

In other words, carrying the variant did not predict which cats developed HCM in this group during the study (1.8 year long).

The study also showed something else. By the end of the study, HCM was present in approximately 40% of the cats.

This highlighted one of the biggest challenges in breeding for HCM: the disease often develops later in life.

Was that the end of the story?

No.

During the study, one cat that had a normal heart scan at the beginning later developed dilated cardiomyopathy (DCM).

That cat carried one copy of the ALMS1 variant. The researchers did not conclude that ALMS1 caused DCM.

However, they pointed out that dilated and restrictive cardiomyopathy are recognised features of Alström syndrome in humans and stated that more cases would be needed to determine whether ALMS1 might also increase the risk of DCM in Sphynx cats.

The authors also suggested that the high frequency of the ALMS1 variant in Sphynx cats may explain why the original 2021 study found a much higher frequency of the variant in affected Sphynx cats than in unaffected cats from other breeds.

Why was this study important?

This was the first study to follow the same Sphynx cats over time, with a median follow-up of 1.8 years.

By the end of the study, HCM was present in approximately 40% of the cats, demonstrating that cats which appeared healthy at the beginning of the study could still develop HCM during follow-up.

Although the researchers found no significant association between ALMS1 and HCM for the tested populations of 55 cats, they concluded that longer follow-up would still be needed before the role of the variant could be fully understood.

2026 – Dargar, Abitbol et al. - Looking beyond cats: what happens inside heart cells?

By 2026, researchers had a different question. Instead of asking “Is ALMS1 associated with HCM?”, they asked:

“Does this genetic variant have any measurable biological effect?”

What did the researchers do?

Rather than studying cats, the team used human induced pluripotent stem cells (hiPSCs). These are special laboratory cells that can be turned into almost any type of cell in the body, including heart muscle cells (cardiomyocytes).

Using gene-editing technology, the researchers introduced the human equivalent of the Sphynx ALMS1 variant into the cells. They then compared them with genetically identical cells that did not carry the variant. This allowed them to study the effect of one single genetic change, without all the other genetic and environmental differences that exist between individual cats.

What did they find?

Cells carrying two copies of the variant produced significantly fewer heart muscle cells than the normal cells. However, the heart muscle cells that did develop appeared structurally and functionally normal.

They beat at a normal rate, they were of normal size, and their internal contracting structures — the parts of a muscle cell that produce each beat — were normally built and arranged.

In other words, the variant appeared to affect how efficiently heart muscle cells formed, but not how the cells functioned once they had developed.

Does this prove ALMS1 causes HCM?

No. This was not a study of cats. It was a laboratory model using human cells.

The researchers demonstrated that the variant has a measurable biological effect, but they did not demonstrate that it causes HCM in Sphynx cats.

What did the authors conclude?

The authors concluded that their findings support further investigation into the biological role of ALMS1.

Importantly, they also repeated the recommendation that ALMS1 should not be used for breeding selection until its pathogenicity has been confirmed by further research.

Why was this study important?

This was the first functional laboratory study of the ALMS1 variant. Previous studies had asked whether the variant was associated with disease. This study asked a different question:

Does the variant do anything at all?

The answer was yes. Whether that biological effect contributes to HCM, another form of cardiomyopathy, or has no clinical consequence in cats remains unknown.

2026 – Sussadee et al.- One more population, the same question

After studies from the United States, Japan, Italy and New Zealand, researchers in Thailand asked the same question once again: Is the ALMS1 variant associated with HCM in Sphynx cats?

What did the researchers do?

The team examined 47 Sphynx cats. Each cat underwent:

• DNA testing for the ALMS1 variant,

• echocardiographic examination by a veterinary cardiologist,

• and statistical analysis comparing genotype with heart measurements and HCM diagnosis.

What did they find?

The ALMS1 variant was present in 44.68% of the cats. However, no statistically significant association was found between the variant and HCM during the study.

There was also no link between the DNA result and the detailed measurements of heart wall thickness and heart function taken during the scans.

What did the authors conclude?

The authors concluded that, in their study population, ALMS1 was unlikely to be the primary cause of HCM.

Importantly, they did not conclude that the variant was harmless or biologically irrelevant. Their findings added further evidence against ALMS1 acting as the primary cause of HCM in that population, but did not classify the variant as benign or biologically irrelevant.

Why was this study important?

This became another independent study that was unable to reproduce the original association reported in 2021.

Its conclusions were also consistent with the 2024 ACMG classification, which continues to classify ALMS1 as a Variant of Uncertain Significance (VUS).

Where does the evidence leave us today?

After five years of research, several things have become clear. The original association reported in 2021 has not been consistently reproduced in independent populations. At the same time, no study has demonstrated that the variant is biologically irrelevant.

Instead, the published evidence has gradually refined our understanding.

Today we know that:

• ALMS1 is not the only genetic factor involved in HCM in Sphynx cats (unchanged since 2021).

• The variant remains classified as a Variant of Uncertain Significance (VUS).

• The biological effect of the variant has been demonstrated in laboratory cells, but its clinical significance in cats remains unknown.

• Taken together, these studies have not provided enough evidence to determine the clinical significance of ALMS1. That is why the variant continues to be classified as a Variant of Uncertain Significance (VUS).

For that reason, describing ALMS1 as either “a proven cause of HCM” or “irrelevant” goes beyond what the published evidence currently supports.

What does this mean for buyers?

If you are buying a Sphynx kitten, the first priority should always be the health of the breeding cats. Ask whether the parents are regularly examined by a veterinary cardiologist, how often they are rescanned, and whether you can see their most recent echocardiography reports.

A DNA test should never replace cardiac screening. However, ALMS1 should not simply be ignored either.

The variant is currently classified as a Variant of Uncertain Significance (VUS). This means that its clinical significance is unknown. At present, science cannot tell us whether the variant increases the risk of disease, has no clinical effect, or influences the heart only under certain genetic or environmental conditions.

Importantly, a VUS is not a permanent classification.

As more studies are completed and more cats are followed over time, the evidence may eventually lead to the variant being reclassified as pathogenic, likely pathogenic, likely benign, or benign.

Today, nobody knows which direction that reclassification will take.

Because the clinical significance of ALMS1 remains unknown, each buyer must decide how comfortable they are with that uncertainty. Some may prefer to avoid it. Others may decide that the current evidence is insufficient for ALMS1 status to influence their choice. Both approaches are reasonable, provided the decision is based on a correct understanding of what a Variant of Uncertain Significance actually means.

What does this mean for breeders?

The current evidence does not support using ALMS1 as a stand-alone breeding test. At the same time, it also does not support ignoring the variant or describing it as biologically irrelevant.

The best available tool for detecting HCM in breeding cats remains regular echocardiographic screening performed by an experienced veterinary cardiologist.

Unlike a DNA test, an echocardiogram examines the heart itself. However, HCM is an age-dependent disease. A cat that has a normal heart scan at one or two years of age may still develop HCM later in life. This was clearly demonstrated in the New Zealand study, where some cats developed HCM during follow-up despite having normal heart scans at the beginning of the study.

For this reason, repeat cardiac screening throughout a breeding cat’s life is far more informative than a single scan performed before the first litter.

Until more evidence becomes available, ALMS1 should be considered one piece of information—not a replacement for regular cardiac screening by a veterinary cardiologist.

References:

Meurs KM, Williams BG, DeProspero D, Friedenberg SG, Malarkey DE, Ezzell JA, Keene BW, Adin DB, DeFrancesco TC, Tou S. A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat. Orphanet Journal of Rare Diseases. 2021;16:108. doi:10.1186/s13023-021-01740-5. PMID: 33639992

Akiyama N, Suzuki R, Saito T, Yuchi Y, Ukawa H, Matsumoto Y. Presence of known feline ALMS1 and MYBPC3 variants in a diverse cohort of cats with hypertrophic cardiomyopathy in Japan. PLoS ONE. 2023;18(4):e0283433. doi:10.1371/journal.pone.0283433. PMID: 37071642

Turba ME, Ferrari P, Milanesi R, Gentilini F, Longeri M. HCM-associated ALMS1 variant: allele drop-out and frequency in Italian Sphynx cats. Animal Genetics. 2023;54:643–646. doi:10.1111/age.13340. PMID: 37345275

Boeykens F, Abitbol M, Anderson H, Dargar T, Ferrari P, Fox PR, Hayward JJ, Häggström J, Davison S, Kittleson MD, van Steenbeek F, Ljungvall I, Lyons LA, Longeri M, Ohlsson Å, Peelman L, Dufaure de Citres J, Smets P, Turba ME, Broeckx BJG. Classification of feline hypertrophic cardiomyopathy-associated gene variants according to the American College of Medical Genetics and Genomics guidelines. Frontiers in Veterinary Science. 2024;11:1327081. PMID: 38371598. (Correction: Frontiers in Veterinary Science. 2024;11:1458433.)

Seo J, Loh Y, Connolly DJ, Luis Fuentes V, Dutton E, Hunt H, Munday JS. Prevalence of hypertrophic cardiomyopathy and ALMS1 variant in Sphynx cats in New Zealand. Animals. 2024;14(18):2629. doi:10.3390/ani14182629. PMID: 39335220

Dargar T, Janin A, Risson V, Lafont E, Valla C, Gache V, Abitbol M. Characterisation of a missense variant of the Alström syndrome centrosome and basal body associated protein (ALMS1) gene associated with cardiomyopathy using induced pluripotent stem cells. Genes. 2026;17(2):227. doi:10.3390/genes17020227

Sussadee M, Jarudecha T, Muikaew R, Supaphom K, Rucksaken R, Sukumolanan P. Prevalence and clinical relevance of Alström syndrome protein 1 gene variant and feline hypertrophic cardiomyopathy in Sphynx cats in Thailand. Animals. 2026;16(12):1815. doi:10.3390/ani16121815

Background: ALMS1 and Alström syndrome in humans

Marshall JD, Beck S, Maffei P, Naggert JK. Alström syndrome. European Journal of Human Genetics. 2007;15:1193–1202. doi:10.1038/sj.ejhg.5201933

Shenje LT, Andersen P, Halushka MK, et al. Mutations in Alström protein impair terminal differentiation of cardiomyocytes. Nature Communications. 2014;5:3416. doi:10.1038/ncomms4416

Louw JJ, Corveleyn A, Jia Y, et al. Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings. European Journal of Medical Genetics. 2014;57:532–535. doi:10.1016/j.ejmg.2014.06.004

Database record

OMIA:002316-9685 — Cardiomyopathy, hypertrophic, ALMS1-related in Felis catus. Online Mendelian Inheritance in Animals. https://www.omia.org