Skewing of X chromosome inactivation in females (which normally achieves dosage compensation) provides a mechanism for some female carriers of pathogenic variations in X-linked recessive genes to manifest disease of varying severity levels, although extreme skewing is rare on a population level 3, 4 this mechanism has previously been inferred to occur in 7.6% of female patients with intellectual disability 5. There are several possible explanations, which are not mutually exclusive. While most X-linked disorders exhibit a profound sex-bias, suggestive of the underlying mode of inheritance, it is frequently observed that both sexes can manifest the same disorder. By contrast, X-linked dominant disorders do not result in such characteristic segregation patterns in pedigrees, and are expected predominantly in females due to the considerably lower mutation rate of the maternally-inherited X chromosome in males 2. The hemizygosity of the X chromosome in males results in a distinctive male-specific pattern of segregation in pedigrees for X-linked recessive disorders, which has facilitated the recognition of such disorders and catalysed the identification of the underlying associated genes 1. Several attributes of X-chromosomal biology render it unique among chromosomes, and have profoundly influenced the landscape of X-linked monogenic disorders. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. For example, the Y-chromosome of Mongolian ruler Genghis Khan (1162-1227 CE), and his male relatives, accounts for ~8% of the Y-chromosome lineage of men in Asia, or about 0.5% world wide (Zerjal et al, 2003).Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Y-chromosome DNA polymorphisms can be used to follow the male lineage in large families or through ancient ancestral lineages. ![]() However, questions remained about the accuracy of this conclusion and in 2004 a genotyping study found a lack of molecular evidence for Y linkage of this trait (Lee et al ). In addition, the daughters of men with the hairy-ear-rim phenotype were unable to pass on the trait. In 1960, the hairy-ear-rim phenotype seen in some Indian families was described as a Y-linked trait (Gates, RR ) based on 20 pedigrees showing father to son transmission. This is the easiest mode of inheritance to identify, but it is one of the rarest because there are so few genes located on the Y-chromosome. Only individuals with a Y chromosome are affected in mammalian Y-linked inheritance and transmission can only occur from a sperm-producing parent. ![]() ![]() On the other hand, one feature of a pedigree that can be used to establish that an inheritance pattern is not X-linked recessive is the presence of an affected XX offspring from unaffected parents because the sperm-parent would have a mutant X and therefore would also have been affected if the trait was X-linked recessive. Note, however, in the small sample sizes typical of human families, it is usually not possible to accurately determine whether one sex is affected more frequently than others. In autosomal dominant and recessive traits, the sex of the individual does not change the probability of being affected, because all individuals have two copies of autosomes. Therefore, in X-linked recessive inheritance, XY individuals, commonly males, tend to be affected more frequently than XX individuals, commonly females, in a population. \)Īny XY individual that inherits an X-linked recessive disease allele will be affected by it (assuming complete penetrance), because they do not have a second copy of the X chromosome to provide a dominant allele.
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