(see also General genetics, General cell biology, prenatal screenings, postnatal screening and multisystem birth defects)

Table of contents :

  • inherited monogenic immune disorders
  • aminoacidopathies
  • collagen diseases / collagenopathies
  • cancer syndromes
  • inherited thesaurismoses / storage diseases
  • congenital disorders of glycosylation (CDG)
  • primary hyperlipidemias / familial hyperlipoproteinemias
  • Web resources
  • Bibliography

  • clinical genetics : the study of the possible genetic factors influencing the occurrence of clinical disorders.

  • The major impact of the completion of the human genome sequence is the understanding of molecular pathophysiology of the different syndromes, from which etiologic therapy will derive. In fact every gene, when mutated, is a potential disease gene, and we end up the new concept of "reverse medicine" (the opposite of reverse genetics / positional cloning : the indirect exploration of a genetic disease by learning the location of the responsible gene, isolating and cloning its DNA, and translating the DNA to determine the protein product. By comparing this product with the product of the normal allele, one can also analyze the nature of the normal protein altered by the mutation), by which we will derive new morbid entities and pathogenic pathways from the knowledge of the structure and function of every gene.  Regardless of the strategy used, the ultimate validation relies on the finding of pathogenic mutations in the suspected gene. The catalog of monogenic ("Mendelian") diseases should be easily completed through simple computer interrogation (in silico cloning). The major challenge today is to decipher the polygenic and multifactorial etiology of common diseases. Anyway apart from environmental influences, there are endogenous factors encrypted in the genome itself, such as modifying genes, or polymorphisms in both coding and non-coding sequences, and some so-called neutral alleles may modulate the expresion of a key protein : it is now clear that monogenic diseases, in which only one gene is affected by an etiological mutation, can no longer be considered as monofactorial disorders. Some genetic diseases do not follow a simple pattern of inheritance and exhibit phenotypic variation. This can be explained as a monogenic disorder that is being affected by the action of nonlinked genetic modifiers, e.g. : From an etiological standpoint, both phenotypic and genetic heterogeneity invalidate the classical nosology, based upon anatomoclinical criteria. Predictive medicine (expecially referring to that arising from knowledge of intrinsic aetiology) is a double-edged sword : beneficial if prevention or cure is possible, detrimental if no action at all can be done !

    The first published study linking gene to disease is often far from the last word on the subject. Marc-Antoine Crocq, a psychiatrist with the Centre Hospitalier de Rouffach in France, learned this firsthand after leading a 1992 study on a mutation in the dopamine D3 receptor in the brainref. The study found that people with 2 copies of the mutation have a schizophrenia risk roughly 2-4 times higher than others. Partly because these ratios were so high, and because the finding came from 2 independent teams, it looked strong. It was also, as it turns out, quite likely wrong. A flood of 50-odd follow up studies, which piled so thickly that they included meta-analyses of meta-analyses, gave inconsistent results. Eventually Crocq and colleagues reviewed all the data and concluded that no statistically significant link existed where they had initially found oneref. Experiences like Crocq's, in which follow-up studies overturn an initial finding of a gene-disease association, are strikingly common. 2 recent studies found that typically, when a finding is first published linking a given gene with a complex disease, there is only roughly a 33% chance that studies will reliably confirm the finding. When they do, they usually find the link is weaker than initially estimatedref1, ref2. The first finding is usually either spurious, or it is true, but it happens to be really exaggerated : there may be no way to predict which new gene-association studies will be verified with multiple replicationref.  The problem is pressing because current trends could exacerbate it : new high-throughput analysis techniques let researchers study many gene-disease associations quickly and cheaply, but also lead to more studies on associations that don't look especially likely at a study's outset. This tends to increase the likelihood of finding spurious links through chance occurrences. By contrast in the old days, it was a big investment to study a hypothesis, and only the best candidates had a shot. Wacholder suggests researchers revise their statistical methods to account for "prior probability," which is a subjective but reasonable measure of how plausible the gene-disease association in question looked before the studyref. Others suggests bigger sample sizes and more family-based studies. These avoid a confounder called population stratification, the tendency of populations to carry high frequencies of both certain genes and certain diseases owing to mere accidents of ancestry : studies with family-based controls and larger sample sizes are more likely to be replicatedref. Researchers should treat any finding cautiously until it's replicated, preferably more than once. No effort to address the problem is completewithout a renewed call to publish more negative findings showing no gene-disease association. Such findings often go unpublished, bolstering false impressions of spurious gene-disease associations. Every study provides a piece of evidence and it needs to be made available somehow to people who are interested.

    The choice of a gene name can have unforeseen consequences in addition to infringement of trademark (e.g. Pokémonref). The quirky sense of humour that researchers display in choosing a gene name often loses much in translation when people facing serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog, Slug or Pokémon. As with the acronym CATCH22 (from 'cardiac anomaly, T-cell deficit, clefting and hypocalcaemia') for chromosome 22q11.2 microdeletions, which was abandoned because of its no-win connotationsref, researchers need to be mindful when naming genes and syndromesref.

    Aetiology :
    Aetiology : loss-of-function mutations
    Symptoms & signs : HSV-1 encephalitis (HSE)
    Aetiology : gain-of-function mutations in STING / TMEM173 leading to a chronic induction of type 1 interferon signalingref
    Symptoms & signs : neonatal-onset systemic inflammation with an elevated erythrocyte sedimentation rate and elevated levels of C-reactive protein, a severe cutaneous vasculopathy leading to extensive tissue loss, and in three patients, major interstitial lung disease. In the skin, there were features of a dense neutrophilic inflammatory infiltrate with blood-vessel damage, and lung biopsies from two patients revealed a lymphocytic inflammatory infiltrate resulting in interstitial fibrosis and emphysematous changes. The authors found that STING was widely expressed, including in endothelial cells and alveolar cells, and that vascular endothelial cells in biopsy samples from lesional skin expressed markers of inflammation. In contrast to the majority of patients with the Aicardi–Goutières syndrome, brain involvement was not noted in patients with SAVI.
    Aetiology : a deficiency of the enzyme flavin-containing monooxygenase 3 (FMO3) in the liver, which oxidises the odorous trimethylamine (TMA) into its nonodorous N-oxide (TMA N-oxide)
    Pathogenesis : large amounts of trimethylamine in urine, sweat and breath
    Symptoms & signs : aroma of fish, which had a profound influence on his life
    Laboratory examination : ratio of TMA-N-oxide to (TMA+TMA-N-oxide) in urine < 1
    Treatment : strict diet. TMA-N-oxide is present in considerable amounts in marine fish and after death is converted to TMA by bacteria resulting in the characteristic smell of rotting
    Prevention :
    As recommended by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicineref3, positive findings on noninvasive prenatal screening must be followed by invasive prenatal diagnostic testing before any irreversible decisions are maderef
    Web resources : Bibliography :
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