Charles II, last of his line, was an imbecile:
The Habsburg King Carlos II of Spain was sadly degenerated with an enormous misshapen head. His Habsburg jaw stood so much out that his two rows of teeth could not meet; he was unable to chew. His tongue was so large that he was barely able to speak. His intellect was similarly disabled. His brief life consisted chiefly of a passage from prolonged infancy to premature senility. Carlos’ family was anxious only to prolong his days and thought little about his education, so that he could barely read or write. He had been fed by wet nurses until the age of 5 or 6 and was not allowed to walk until almost fully grown. Even then, he was unable to walk properly, because his legs would not support him and he fell several times. His body remained that of an invalid child. The nature of his upbringing, the inadequacy of his education, the stiff etiquette of his court, his dependence upon his mother and his superstition helped to create a mentally retarded and hypersensitive monarch.
A new PLoS One paper dives into the genetics:
The kings of the Spanish Habsburg dynasty (1516-1700) frequently married close relatives in such a way that uncle-niece, first cousins and other consanguineous unions were prevalent in that dynasty. In the historical literature, it has been suggested that inbreeding was a major cause responsible for the extinction of the dynasty when the king Charles II, physically and mentally disabled, died in 1700 and no children were born from his two marriages, but this hypothesis has not been examined from a genetic perspective. In this article, this hypothesis is checked by computing the inbreeding coefficient (F) of the Spanish Habsburg kings from an extended pedigree up to 16 generations in depth and involving more than 3,000 individuals. The inbreeding coefficient of the Spanish Habsburg kings increased strongly along generations from 0.025 for king Philip I, the founder of the dynasty, to 0.254 for Charles II and several members of the dynasty had inbreeding coefficients higher than 0.20. In addition to inbreeding due to unions between close relatives, ancestral inbreeding from multiple remote ancestors makes a substantial contribution to the inbreeding coefficient of most kings. A statistically significant inbreeding depression for survival to 10 years is detected in the progenies of the Spanish Habsburg kings. The results indicate that inbreeding at the level of first cousin (F = 0.0625) exerted an adverse effect on survival of 17.8%612.3. It is speculated that the simultaneous occurrence in Charles II (F = 0.254) of two different genetic disorders: combined pituitary hormone deficiency and distal renal tubular acidosis, determined by recessive alleles at two unlinked loci, could explain most of the complex clinical profile of this king, including his impotence/infertility which in last instance led to the extinction of the dynasty.
Razib Khan explains:
F, or the coefficient of inbreeding, is critical here. Charles II was not simply the offspring of a first cousin marriage, he was the culmination of a repeated instances of cousin marriage over several generations. [...] In other words, Charles II was moderately more inbred than the average among the offspring from brother-sister matings!
The Spanish Habsburgs had higher infant mortality than Spanish commoners.
This all ties into Daenerys’s first chapter in Game of Thrones:
Despite the seemingly obvious drawbacks of hemophilia, porphyria, and flipper babies, royal incest was a historical phenomenon in many cultures. The Pharoahs of Egypt most closely resemble the Targaryen pattern, although they tended to stick to half-brother/half-sister marriages until the Ptolmys, who went in for direct brother-to-sister marriages. The Incas and the royal house of Hawaii also went in for brother-sister marriages. In medieval Europe, direct incest was both illegal and condemned by the Church, with the bizarre case of Jean V of Armagnac the only case I could find of a brother-sister marriage.
The danger of this practice can be seen in the case of the House of Hapsburg, in both its Austrian and Spanish lines was well-known for “consanguineous marriage,” including one marriage of an uncle to a niece. Even avoiding direct incest of brothers and sisters or fathers and daughters, they still succeeded in increasing the inbreeding coefficient tenfold to the point of parent-child and brother-sister levels. This lead to recurrent problems with deformity, infertility/importance, mental disorders and retardation, and other genetic abnormalities.
Given these problems, it’s surprising the Targaryens lasted as long as they did with so few obviously deformed offspring, given how brother-sister marriage increases the risks of genetic disorders beyond the levels associated with marrying first cousins. It’s possible that, like some royal houses engaged in direct incest, they practiced infanticide to weed out obvious cases of maladaptive traits. This might explain how so many Targaryens are described as having been beautiful (although part of that may be the association between Targaryen traits like silver hair and purple eyes with power and therefore beauty) — although they clearly missed a spot when it came to Maelys the Monstrous. Their track record when it comes to weeding out less obvious conditions that might have affected the mind is less good (although it’s hard to separate nature vs. nuture in these circumstances): Maegor the Cruel, Aerion Brightflame, Rhaegel Targaryen, Mad King Aerys II, the list is hardly inspiring.
The marriage between Daenerys and Khal Drogo brings up an interesting historical point — it’s probable that the Dothraki are patterned not off the Mongols, but rather the Huns, and Khal Drogo himself on that most famous Hun, Attila, and Daenerys off of the Roman princess Honoria. In 450 AD, the willful and infamous lady Honoria, sister to the weak Emperor Valentinian III, sent a plea for help to Attila in overcoming her brother, and offered in exchange her hand in marriage — and half of Gaul. At the time, Attila was one of the greatest warlords in the known world, extracting tribune from Constantinople, laying waste to the Balkans, and smashing Roman armies. To win Honoria’s hand and secure her position, Attila invaded Gaul, capturing Metz, Rheims, and Paris — before being defeated at the Battle of Châlons. When Valentinian III denied him his bride, Attila invaded Italy and practically burnt it to the ground — the city of Venice was founded out in the lagoon by refugees trying to get away from his horsemen. So like Khal Drogo, Attila would lay kingdoms to waste for the sake of his bride — and like Drogo, Attila would die no warriors death, but from a most minor injury — he suffered a massive nosebleed while intoxicated, and choked to death on his own blood.