Mental retardation: an avalanche of genes.
To start with isolated mental retardation (i.e. patients which are affected by mental retardation only, with no other clinical signs or very mild additional traits) to finish with highly syndromic cognitive delay in patients who shows several malformations and/or metabolic imbalances, mental retardation is possibly the largest chapter in rare genetic disorders. Today, we know thousands of genes of which mutations may cause mental retardation. If we also include genetic conditions which may be characterized by mental retardation only in some patients, due to the so called variable expressivity, the group of genes becomes even larger.
X-linked and autosomal isolated mental retardation
X-linked mental retardation (which predominantly affects males, but may be also found in females) is almost considered the paradigm of isolated mental retardation. At present, the OMIM database contains at least 49 different types of X-linked mental retardation, from MRX1 (caused by mutation in the IQSEC2 gene) to MRX101 (probably caused by mutation in the MID2 gene), with several subtypes in the middle (with ot without known gene) (see here the phenotypic series of mental retardation, nonsyndromic, X-linked).
Coming to autosomal recessive nonsyndromic mental retardation, we have 65 entries, whereas for autosomal dominant nonsyndromic mental retardation, which is often caused by de novo mutations, we have additional 65 entries.
So, just looking at the OMIM phenotypic series for X-linked and autosomal forms of isolated cognitive delay, we reach almost 200 different genetic subtypes to be tested (although the genes are not known for all subtypes yet, many have been identified and can be fully sequenced).
Syndromic mental retardation
Now it’s difficult: I am pretty sure no Geneticist in the world can give the precise number of monogenic conditions which are (or may be) associated with cognitive delay of any level, from mild to severe. Let’s give it a try: if we just type “mental retardation” in the OMIM advanced search for Clinical Synopses, we get 1,531 results. These results will certainly include both nonsyndromic (already discussed above) and syndromic conditions with mental retardation, but gives us an idea of how extended this chapter is. Typing “cognitive impairment” turns out in other 593 results. Typing “speech delay” leads to 1,287 results and typing “intellectual development” gives back 1,345 results.
Non-monogenic mental retardation
Besides monogenic disorders, i.e. conditions which are caused by a single mutation in a single gene, as the Cytogeneticists colleagues know very well, there’s a plethora of chromosomal conditions and syndromes which may include mental retardation, from mild to severe, most of which are characterized by high clinical variability. Such disorders are caused by the loss, disruption or gain of entire pieces of chromosomes, hence containing more than one gene. This kind of conditions was used to be screened by array-CGH, which has been for years the first indication for genetic testing in people with mental retardation. Nowadays, while array-CGH still remains the gold standard, some laboratories started to substitute array-CGH with CNV analysis on NGS data.
Coming to practice: multigene panels, whole exome sequencing and whole genome sequencing for the diagnosis of intellectual impairment.
Given the extremely high number of genes which may be associated with mental retardation, the question arises: is it better to do a multigene panel (e.g. a 100-300 gene panel) first or is it more convenient to go straight to the entire exome analysis?
Panels for mental retardation were very used in the past, when whole exome sequencing or whole genome sequencing still posed problems of costs as well as Bioinformatics and human work burden in large data analysis. Still today, panels for cognitive delay are very much requested, due to both habitual practice and to structured lab offers which tend to remain in place for years. However, it must be said that some groups, like Breda Genetics since its very beginning, are now offering panels which are based on whole exome or whole genome sequencing: they sequence the exome or the entire genome, and based on that they analyze just the panel genes. This enables two things: 1. maximum plasticity in panel composition and 2. superfast upgrade to whole exome data analysis, if the panel is negative.
The best choice?
1. Do you have a well defined clinical suspicion for a known syndrome or a group of disorders with mental retardation (e.g. Joubert syndrome, where every patient has the molar tooth sign, a distinctive cerebellar and brain stem malformation)? Then you can choose a multigene panel (it’s much better if the panel is based on whole exome or whole genome sequencing).
2. Are you missing any clue about the possible clinical diagnosis (or even suspect a new disorder)? Then we strongly recommend that you opt immediately for whole exome sequencing or even whole genome sequencing (on average, whole genome sequencing may increase the mutation detection rate of 5-6% in respect to whole exome sequencing: if you want to learn more about the differences between whole exome and whole genome sequencing, read our post here). Before or in parallel, we also recommend performing array-CGH to scan for large chromosomal imbalances. The screening for chromosomal disorders may also be done later by performing algorithmic CNV analysis on the sequencing data from whole exome or whole genome (algorithmic CNV analysis shows an even higher resolution than array-CGH, although the latter still has the highest values of sensitivity and specificity).