DEVELOPMENTAL DELAY, INTELLECTUAL DISABILITY AND SYNDROMOLOGY

The investigation of the genetic causes of diseases presenting with intellectual disability, with syndromic features or developmental delay, has been a key area of research and of our diagnostic efforts.

Starting, historically, from the application of high resolution peripheral blood karyotype in the early ’80s, which was the first and main test in all children and individuals with intellectual disability and/or developmental delay, we gradually proceeded to apply molecular cytogenetic techniques through fluorescent in situ hybridization (FISH) for the detection of several syndromes associated with intellectual disability, then through the application of molecular genetic techniques for the diagnosis of Fragile X syndrome (FRAX) and finally to the pioneering applications in our country in 2007 of high resolution molecular karyotype-arrayCGH (aCGH).

These efforts culminated in the introduction of the analysis of all human genes (Whole Exome Sequencing – WES) in 2011, through the new technology of massive parallel sequencing (Next Generation Sequencing – NGS).

Over the last 30 years of operations, InterGenetics has investigated more than 2000 cases through high resolution peripheral blood karyotype and in situ fluorescent hybridization (FISH) and also has performed more than 480 molecular genetics tests for Fragile X (FRAX) and more than 200 genetic tests for mental retardation utilizing high-resolution aCGH.

Recently, InterGenetics has evolved into a reference center for this very important and sensitive type of disorders, concerning mainly young children, by adding new genomic testing options in order to uncover the underlying genetic defects in cognitive and developmental disabilities, such as genomic analysis all human genes (Whole Exome Sequencing – WES) and the genomic analysis of all X-linked disease genes associated with mental retardation in males (a comprehensive investigation of X-linked mental retardation).

It is also worth noting that InterGenetics, recognizing the importance of prevention of these diseases, pioneered in 2012 the incorporation of genetic screening for Fragile X-FRAXA syndrome in all cases of prenatal chromosomal diagnosis, thus diagnosing any affected male fetuses. In this context we have tested so far more than 1000 embryos and have already prevented the birth of affected children, due to the mother being, unknowingly, a carrier of the disease.

Joined by experienced clinicians and drawing additional experience from the investigation of genetic syndromes, applied by InterGenetics since 2002, we believe that we provide an up to date and comprehensive approach to the investigation of patients and for the safe guidance of families burdened with such problems.

It is estimated that about 4% of children have a genetic disease or syndrome, which may include developmental delay and/or intellectual disability. Although we make every effort to diagnose these problems in as many children as possible through prenatal molecular karyotype or other new genomic tests, such as the Fetalis^®, there still remains a significant proportion of affected children which trouble both parents and physicians regarding the cause.

In particular, intellectual disability in humans is divided into mild, moderate and severe and occurs with a frequency of about 2-3% in the general population, typically with an undiagnosed etiology.

Many types are inherited in the family, while idiopathic-sporadic intellectual disability, without any previous family history, is the most common type. Mental retardation may even be caused by non-genetic factors, such as infections, perinatal asphyxia, etc .. The most severe forms of mental retardation are considered to have a genetic cause, but the exact genetic defect remains unknown in 55-60 % of patients.

Understanding the genetic cause of intellectual disability can benefit patients and their families, since the diagnosis may provide information regarding prognosis, exclude further unnecessary tests and may lead to proper management. Moreover, the diagnosis often facilitates access to personalized medicine and supportive care.

Meanwhile, family members can benefit from knowledge of recurrence risks and the provision of appropriate reproductive options or possible prenatal diagnosis.

The incidence of X-linked mental retardation (XLMR) is estimated to be about 1 in 500 males. To date, there are more than 200 different forms and approximately 165 are classified as syndromic forms, characterized by specific biochemical, morphological and neurological defects associated with mental retardation.

The most common cause of XLMR is due to a pathogenic expansion of a trinucleotide repeat (triplet repeat) in the untranslated region of the FMR1 gene, leading to the expression of Fragile-X syndrome (FRAXA). More than 100 additional genes-loci which are involved in XLMR have now been identified through genetic linkage analysis, by direct genetic analysis of gene mutations or through cytogenetic studies.

Each one of these loci-genes account for only a small number of families/cases with XLMR and despite this success, a significant number of genes responsible for XLMR have not yet been revealed through standard genetic analysis.

Thus, intellectual disability in general and XLMR in particular are classic examples of genetic heterogeneity for a relatively common disease.

Another related condition, global developmental delay (GDD), occurs in 1-2% of the general population and is often encountered in the field of pediatric neurology. New technological developments and our increased understanding of genetic disorders have led to changes in the diagnostic approaches of a child with unexplained developmental delay.

High-resolution chromosomal microarray analysis, known as molecular karyotype or arrayCGH, is now the first line genetic test for the evaluation of these patients, offering significantly increased diagnostic yield, ranging from 10-30% depending on the case.

Today, classical karyotype analysis is often used to supplement molecular karyotype and is no longer the test of choice for patients with developmental delay. The presence or absence of certain clinical features, such as: microcephaly or macrocephaly, seizures, autism, abnormal clinical neurological findings and dysmorphic features, may be used to direct the type of genetic testing.

Very recently, the availability of new genomic technologies of massive parallel sequencing (Next Generation Sequencing – NGS) permits a rapid analysis of hundreds to thousands of genes associated with development disorders and/or intellectual disability.

Moreover, the clinical application of Whole Exome Sequencing (WES) offers new possibilities for the evaluation of individuals with developmental or mental disabilities, who remain undiagnosed through other genetic tests.

In general, the discovery of the underlying genetic cause of intellectual disability is not easy, since many different syndromes and hereditary diseases include intellectual disability as a clinical symptom.

Modern genetic diagnosis includes a series of tests designed to reveal the genetic causes of intellectual disability in an affected person and these tests are carefully selected and implemented following appropriate clinical genetic assessment of each case, always in cooperation with clinical specialists/physicians, for e.g. pediatricians, pediatric neurologists and also other specialties, such as orthopedists, cardiologists, ophthalmologists, otolaryngologists, et..

Discovering the genetic damage associated with intellectual disability is a valuable (if not required) tool for the further management of the case by the referring physician. Without this knowledge it is difficult to offer genetic counseling regarding the patient, the reproductive choices of the couple but also for the overall impact on the family.

It is essential, therefore, that genetic testing be recommended and offered in depth and in detail, covering all possible scenarios, but always after proper evaluation of the clinical data by a specialist and a clinical geneticist.

Proper clinical genetic evaluation of a patient and genetic counseling, both before and after testing, are essential in order to determine the most appropriate testing and to communicate correctly the concepts of pathological and normal.

• Creation of the family history with access to all health-related problems of the patient
• Analysis of the family history with respect to the genetic risk
• Assessment and explanation of the risk for the existence of a genetic abnormality in the family
• Discussion on the nature of the disease, including the contribution of hereditary factors
• Discussion regarding the available genetic testing options and explanation of the different expected types of results
• Relay the advantages and limitations of each option and confirm that the parents have understood the implications