lower organisms [1], its potential to contribute to clinical heterogeneity in human disease is seldom considered. Evidence of interallelic complementation at clinically relevant loci is limited to biochemical and cell-based studies of a handful of metabolic disorders with defects in enzymes including propinyl-CoA carboxylase [2], argininosuccinate lyase [3], galactose-1-phosphate uridylyltransferase [4], and methylmalonyl CoA mutase [5].
Compound heterozygotes are individuals carrying two different mutant alleles of the same gene. In the absence of a dominant (wild-type [wt]) allele, genetic interactions between recessive alleles (referred to here as “biallelic” effects) could result in different phenotypic outcomes including interallelic complementation. Although amelioration of disease symptoms by interallelic complementation would create an ascertainment bias in the clinic, the lack of evidence concerning interallelic complementation or other biallelic effects in human disease is likely caused by the difficulty in distinguishing such effects from environment and genetic background.
XPD encodes one of the two helicase components of basal transcription/DNA repair factor IIH (TFIIH), a ten-subunit, multifunctional complex that is essential for multiple processes, including basal transcription initiation and DNA damage repair via the nucleotide excision repair (NER) pathway [6,7]. Alterations in XPD resulting in defective TFIIH function are associated with UV-sensitive, multisystem disorders including xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD) [8–10]. XP is marked by sun-induce