Genetic Traits of an Island Population: Why Some Inherited Disorders Are More Frequent in Malta

Malta is known not only for its rich history and culture, but also for the distinctive genetic profile of its people. A small, historically isolated population combined with frequent consanguineous marriages and the so-called founder effect has led to certain genetic and mental disorders occurring more often here than in mainland Europe. This article explores the historical causes behind this phenomenon, highlights specific conditions more common among Maltese people, and explains the genetic mechanisms that play a crucial role in small populations. Finally, Malta will be compared with other isolated populations, such as those in Iceland and Sardinia.

Historical isolation, a small population and consanguineous marriage

Malta belongs among countries with small populations – today, roughly half a million people live on the islands. For many centuries the Maltese population was largely isolated, because, as an island in the middle of the Mediterranean, it did not receive large numbers of new settlers. The population therefore descended from a relatively narrow circle of ancestors. Approximately 300–400 years ago the population began to grow rapidly from a much smaller base, and this was precisely when the founder effects became evident – a genetic phenomenon whereby the characteristics of a handful of original individuals become disproportionately represented in the new population. The result is that some genetic variants are unusually common among Maltese people today, while others never entered their gene pool at all.

Historically, Malta was predominantly rural, with isolated villages – and the island of Gozo was even more closed. Choices of partner were therefore limited, and marriages between more distant relatives (for example, first cousins) were not unusual. The Catholic Church did restrict such unions by requiring a special permission – a dispensation – yet even so, they remained fairly common well into the nineteenth century.

As early as 1874, the Maltese physician Gavino Gulia criticised the high frequency of consanguineous marriages and warned that they contributed to poor health among Maltese people. The statistics bear him out: in the late nineteenth century such marriages accounted for several per cent of all unions.

Interestingly, their share rose again during the Second World War – in 1943 they represented about 4.4 per cent of all marriages. People from bombed areas often sought refuge with relatives, which naturally led to a higher rate of cousin marriages. Only after the war, with modernisation and greater mobility, did the prevalence of consanguineous unions drop sharply.

The founder effect and genetic drift were two key mechanisms shaping the Maltese population. The founder effect occurs when a new population is established by a small number of individuals. They pass on only a limited portion of the original gene pool, which then becomes disproportionately represented in subsequent generations. The outcome is reduced genetic diversity and unusually high frequencies of certain variants compared with the source population.

At the same time, genetic drift – random fluctuations in allele frequencies between generations – exerts a stronger influence in small populations. In such a limited “sample” of parents, chance alone can cause neutral or rare variants to spread, or conversely to disappear altogether.

Another factor was consanguinity, which increases the probability that offspring inherit two identical copies of a gene. This raises the risk that recessive defects, which would remain hidden in a more diverse population, will be expressed.

In short, a small, isolated population tends to display low genetic diversity, more frequent consanguinity and greater sensitivity to genetic drift. In Malta these factors historically combined and significantly shaped the gene pool.

Hereditary Disorders Observed More Frequently in the Maltese Population

As a consequence of these factors, certain genetic diseases and disorders occur in Malta more often than elsewhere. This does not mean that Maltese people generally have poorer health – rather, a handful of otherwise rare conditions are relatively more common here because of the genetic mechanisms described. The following examples draw on published medical research.

Beta-thalassaemia (Mediterranean anaemia)

Beta-thalassaemia is an inherited disorder of blood formation and is among the most common genetically determined diseases in Malta. Approximately 1.8 per cent of Maltese people are carriers, which is higher than in Northern Europe but comparable with the wider Mediterranean region. The explanation lies in history: the mutation once conferred partial protection against malaria – similar to the better-known sickle-cell trait.

Today, several dozen patients in Malta live with the most severe form, beta-thalassaemia major, requiring regular blood transfusions from childhood. Thanks to antenatal screening introduced in the 1990s, high-risk couples can now be identified in time, which has largely prevented the most severe cases.

Historical studies indicate higher prevalence in the past: in the 1960s, rates among Maltese children ranged between 7–9 per cent (with higher figures on Gozo). Moreover, a single, specific mutation of the beta-globin gene (IVS I-6 T→C) predominates in the Maltese population, accounting for up to 78 per cent of all cases. Such uniformity is unusual in genetic disorders and points to a strong founder effect – probably originating from a single ancestor, rather than multiple different mutations as seen in other countries.

Phenylketonuria (PKU) and related metabolic disorders

Phenylketonuria (PKU) is an inherited disorder of the metabolism of the amino acid phenylalanine. Without early treatment with a strict diet, it leads to severe intellectual disability. For that reason, most countries routinely screen newborns with a heel-prick blood test shortly after birth. In Malta, however, a mandatory universal screening programme for PKU was long absent – testing occurred only within pilot projects or for infants with a family history. Around 2018–2021, the state prepared projects and tenders to introduce screening, but available sources have not yet confirmed that universal screening actually began operating.

Although case numbers are small, there is a notable peculiarity: in Malta a different defect predominates compared with classic PKU. Between 1996 and 2015, five children from three related families were diagnosed with a rare deficiency of the enzyme dihydropteridine reductase (DHPR), which is linked to the metabolism of tetrahydrobiopterin (BH4). Only a single child over the same period had classic PKU caused by deficiency of phenylalanine hydroxylase. Put simply: in Malta, instead of the usual form of PKU there is a more frequent rare variant that is scarcely seen elsewhere – due to island isolation and more frequent consanguinity.

Here, the founder effect and consanguinity have led to a relatively higher frequency of BH4-dependent forms of PKU, whereas the common “classic” variant is comparatively rare. It is estimated that up to 3.3 per cent of the Maltese population are carriers of a mutation causing DHPR deficiency – a surprisingly high proportion for an otherwise extremely rare disorder. (For comparison: carrier frequency for classic PKU mutations in Europe is typically around 2–3 per cent.)

Because screening was missing for a long time, Maltese children with this defect were diagnosed late and unfortunately suffered irreversible brain damage. They experience developmental delay, epilepsy and other neurological problems, even with treatment. This example illustrates how, in a small isolated population, increased frequency of a rare metabolic defect can lead to a higher number of children with severe intellectual disability.

Other rare hereditary diseases

As a result of the factors described above, certain genetic diseases and disorders occur in Malta more frequently than elsewhere. This does not mean that Maltese people generally have poorer health – rather, a small number of otherwise rare conditions are relatively more common here due to the genetic mechanisms mentioned. Below are examples of such conditions, documented by specialist research findings.

Hidradenitis suppurativa (HS)

One example is hidradenitis suppurativa (HS) – a chronic inflammatory skin disease characterised by painful abscesses and cysts. Globally it affects only about 0.05 per cent of the population, whereas in Malta estimates reach up to 1.5 per cent – a thirtyfold higher prevalence.

Cystinuria

Another example is cystinuria, an inherited metabolic disorder associated with kidney stone formation. Among Maltese patients, a rare p.Y151N mutation in the SLC3A1 gene has been identified – scarcely seen elsewhere (in European populations about 1 in 100 people are carriers of any cystinuria-related mutation). In Malta, however, this particular mutation dominates: most patients with cystinuria carry precisely this “founder” variant, which likely arrived in the islands in the Middle Ages (perhaps from Sicily) and gradually spread.

Autosomal dominant polycystic kidney disease (ADPKD)

Similarly, for ADPKD, clinicians found that nearly one-third of Maltese patients share the same mutation in the PKD2 gene. Analyses indicate that this is again a variant inherited from a common ancestor – another illustration of the founder effect.

Why small populations behave differently: founder effect, genetic drift and consanguinity

In the previous section, we repeatedly encountered the terms founder effect, genetic drift and consanguinity. These mechanisms explain why some disorders occur more frequently in Malta than elsewhere. They are not unique to Malta – they operate in any small, isolated population. To better understand their impact, let us briefly summarise them.

Founder effect

The founder effect arises when a new population is established by only a few individuals. These “founders” bring with them a limited set of genetic variants (alleles) compared with the larger source population. Some genes – including those that were originally rare – can therefore become unexpectedly common in the new group.

The result is a loss of genetic diversity and a different distribution of variants. A classic illustration would be the settlement of a deserted island by a small group of sailors, or the isolation of a mountain valley by a few families after a landslide – their descendants will chiefly carry the genes of those founders, including any mutations.

In Malta, the founder effect has been demonstrated, for example, in cystinuria and thalassaemia, where most cases trace back to a single common ancestor and the mutation spread widely in the small population.

Genetic drift

Genetic drift is random fluctuation in allele frequencies within a population. In large populations, frequencies remain roughly stable – even if some carriers of a mutation have no children, others will, and the overall proportion stays similar.

In a small community it is very different. Imagine a village of fifty people: if a rare mutation is present in just one person, it may disappear entirely over a few generations – for instance, if carriers happen not to have children. Just as easily, the mutation may spread if carriers have large families. Chance plays a much larger role than in a big population.

In isolated communities, genetic drift therefore causes some alleles to become fixed (common) while others are lost. In Malta, this effect has been observed, for example, in mitochondrial DNA and Y-chromosomes: haplotypes that are rare elsewhere reach unexpectedly high frequencies here – purely due to chance and long-term isolation.

Consanguineous marriage

When close relatives marry (for example, first cousins), the probability rises that their children inherit the same variant from both parents – because both share an ancestor. This increases homozygosity in the population. For most genes this is harmless, but if both parents carry the same recessive mutation, each child has a one-in-four risk of inheriting the defect from both parents and manifesting the disease.

In small, isolated populations there is also “cryptic” relatedness within the community – people are related even when they do not realise it. The result is a higher incidence of recessive diseases, congenital defects and sometimes lower overall population fitness.

Studies repeatedly show that consanguinity increases the risk of various congenital disabilities – for example, intellectual impairment, deafness or metabolic defects. In Malta, historical consanguinity likely contributed to the higher frequency of some intellectual and metabolic disorders (e.g., phenylketonuria). Even though consanguineous marriages are rare today, the genetic burden from the past can persist for generations.

Comparing Malta with other isolated populations

Malta is by no means the only example of a small, isolated community with unusual genetic features. Similar phenomena appear elsewhere and are a valuable source of insight for researchers – they help us understand how genetics influences the emergence and spread of disease. Below are several informative parallels.

Iceland (genetic isolate and BRCA2)

Iceland has roughly 370,000 inhabitants and its population arose about 1,100 years ago through the colonisation by a few thousand Vikings and Celts. Owing to long-term isolation and small size, it is highly homogeneous and bears strong founder effects.

For example, certain mutations associated with breast cancer (e.g., a founder mutation in BRCA2) and other hereditary diseases are more common in Iceland than in mainland Europe, while other variants are almost absent.

Icelandic researchers have mapped pedigrees for the entire population and shown that isolated island populations are exceptionally valuable for understanding the genetics of disease. Genetic uniformity facilitates the search for mutations that also contribute to common complex diseases.

According to studies, about 1 in 25 Icelanders carry an “actionable” mutation (a variant that increases the risk of a serious disease but can be detected and mitigated by prevention or treatment) – a change in DNA that shortens life expectancy.

Sardinia (autoimmunity in an isolated population)

Sardinia is a large Mediterranean island with about 1.6 million inhabitants. Although not a tiny population, gene flow with the mainland was limited for centuries. Sardinia is therefore considered an ancient genetic isolate – its inhabitants have lived there for thousands of years with minimal immigration.

The result is that the Sardinian population harbours specific genetic variants that are very rare elsewhere but, through genetic drift or selection, have risen to relatively high frequencies on the island.

This distinctive gene pool is reflected in disease epidemiology. Sardinia has an unusually high prevalence of autoimmune diseases, especially multiple sclerosis and type 1 diabetes – despite its southern European location, where such conditions are usually less common.

Genetic “islands” in the mountains (Alps, micro-regions)

Isolated communities need not be on islands – they often arise on the mainland in remote mountain valleys. These “genetic islands” operate similarly: for generations, people married mainly within the same village, and consanguinity increased the frequency of certain hereditary disorders.

In Alpine valleys of Switzerland, Austria and Italy, for instance, marriages within a single village were common historically, and people seldom sought partners from outside their region. Records report high rates of congenital thyroid disorders and deaf-mutism. Today we know that part of the cause was iodine deficiency (endemic goitre and cretinism), but genetic isolation and consanguinity may also have played a role.

Across northern Italy and elsewhere, entire micro-regions with unusually frequent rare syndromes have been described – again as a consequence of consanguinity and genetic drift in small communities.

A striking example is Tristan da Cunha in the South Atlantic. The population numbers only about 260 people and descends from just 15 founders. Only a few surnames prevail to this day, and locals have extremely high rates of hereditary asthma and glaucoma – a clear consequence of the founder effect in a very small gene pool.

In conclusion

Malta offers a clear example of how population history shapes present-day health. Long isolation, a small gene pool and consanguineous marriage have left signatures in Maltese genetics, reflected in the higher frequency of several specific hereditary disorders. This is not a reason for stigmatisation; on the contrary, understanding these links supports prevention, early diagnosis and more considerate communication.

If you have a family history of a hereditary condition, consider genetic counselling. From a genetic standpoint, a more diverse parental background generally reduces the likelihood of recessive diseases in children. Finally, prevention and timely screening – whether antenatal, newborn or targeted by family history – can save not only health but also substantial financial resources.

Frequently Asked Questions About Genetics in Malta