GeNeViSTA

1 Introduction

Neurodevelopmental disorders affect around 3-5% of the population. These are heterogeneous in etiology and more befittingly termed “symptom complexes”. The various disorders presenting with intellectual disability may be congenital or acquired, sporadic or familial, syndromic or non-syndromic. Severe neurodevelopmental disorders are mostly genetic in origin and may be due to a molecular defect at the chromosomal or single gene level or due to epigenetic abnormalities. Till date more than 450 genes have been implicated in intellectual disability. One may wonder as to what is the need for an etiological diagnosis when majority of these cases cannot be cured. However, diagnosis is a key element in the management of the patient, for explaining the course and prognosis, and for provision of appropriate care and support system. It precludes subjecting the patient to unnecessary and redundant tests and interventions. It is essential for proper counseling of the family regarding the recurrence risks and prenatal diagnosis, and also for access to research treatment protocols. The family’s “need to know” has an enormous emotional impact and cannot be ignored. The elucidation of the underlying molecular abnormalities is another important step towards developing treatment strategies (Willemsen et al., 2014).

2 Diagnostic Approaches

Various diagnostic practice guidelines are available for evaluation of patients with neurodevelopmental disorders and consist of clinical evaluation, neuroimaging, metabolic profile, cerebrospinal fluid examination and specific genetic tests dictated by the clinico-biochemical phenotype (Michelson et al., 2011; Moeschler et al., 2014). Cytogenetic microarray which is now considered to be the first line test in the diagnosis of non-specific intellectual disability has a yield of 10-20%. This “diagnostic odyssey” lasts many years and more than half of the patients never receive an etiological diagnosis, thereby adding to the pain and disappointment besides the cost incurred by the family. In a survey of patients with rare diseases it was found that for 25% of participants, the time to diagnosis was extensive, ranging from 5 to 30 years, and during that time 40% received an incorrect diagnosis (Sawyer et al., 2016).

3 Whole Exome Sequencing and its Utility in Neurodevelopmental Disorders

With the advent of whole exome sequencing (WES), there came a paradigm shift in the approach to the diagnosis of rare diseases, with timely diagnosis of genetic diseases and discovery of new disease-causing genes. WES uses a high throughput sequencing technique of next generation sequencing (NGS) to sequence coding regions of all genes in the human genome. This helps to identify the causative gene/ mutation even if the clinical evaluation and supportive investigations do not provide any clue to the etiology and the causative genetic defect. This approach is being used for all genetic phenotypes with known or unknown causative genes. The study by Retterer et al. (2016) on the use of WES on 3040 consecutive cases gave a high diagnostic yield for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Here, we review the diagnostic yield of WES in neurodevelopmental disorders. In cases of moderate to severe neurodevelopmental disorders, different studies have reported a diagnostic yield ranging from 16-45% using WES (de Ligt et al., 2012; Yang et al, 2013; Yang et al., 2014; Sawyer et al., 2016). WES out-performs conventional approaches in the diagnosis of disorders with genetic heterogeneity with phenotypic variability and poor specificity. Besides its utility in the diagnosis of ultra-rare conditions and novel gene discovery, it also has an impact on expanding the phenotypic spectrum of already known syndromes. Most importantly, WES allows for re-assessment of data in the light of new knowledge, thus providing additional diagnostic results over years without significant extra costs. WES is an effective approach in the evaluation of cases with sporadic non-specific ID using family based strategy (child-parents trios) with yields of 35-55% (Willemsen et al., 2014). The use of WES is not only restricted to identification of these de novo variants but its emerging widespread use in predominantly consanguineous populations has led to the expansion of the repertoire of genes causing autosomal recessive neurodevelopmental disorders. Recently, a study in 121 consanguineous families identified pathogenic variants in 68, out of which a novel gene was implicated as causative in 30 (Riazuddin et al., 2016). The diagnostic yield of WES in cohorts with neurodevelopmental disorders in various studies has been summarized in Table 1. While the effectiveness of WES in the diagnosis of intellectual disability has been proven beyond doubt, the optimal timing of when it should be done is still debatable. Whether WES should be at the first appointment if clinically indicated or after the initial tests are normal (e.g. first tier of genes ruled out) or towards the end of the diagnostic odyssey (e.g. after extensive, possibly invasive tests have occurred), needs to be evaluated. The newer school advocating use of WES as a first-tier test have undertaken some studies using genomic tools (WES alone or with molecular karyotyping) in the diagnosis of ID patients. They have reported diagnostic yields of 32-58% (Anazi et al., 2016; Thevenon et al., 2016). Diagnostic yield as high as 91% has been reported in consanguineous families (Shaheen et al., 2016). Notably, many of the molecular defects were not suspected clinically, highlighting the power of this tool to overcome the limitations of clinical phenotyping. This has set a trend of “reverse phenotyping”, whereby the success of identification of clinical recognizable ID syndromes will no longer be highly dependent on clinical expertise of syndrome recognition, causing a shift from a “phenotype first’’ to a “genotype first’’ approach. Besides, the impact on families in ending the expensive, often invasive, and stressful diagnostic odyssey cannot be overemphasized. However, in both the cases detailed phenotyping remains a very important step in the diagnostic approach to a case with a neurodevelopmental disorder and the clinician has a very important role to play in manually judging the candidate sequence variations identified by mining the exome data.