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Neurodevelopmental disorders – discovering the underlying cause and how genomic data analysis ended a 21-year diagnostic odyssey

What are neurodevelopmental disorders?

Neurodevelopmental disorders can be described as a group of disorders in which the development of the central nervous system has been disrupted. They are often detected in early infancy but can be identified shortly after birth or even observed prenatally during routine ultrasound screening.

Neurodevelopmental disorders can manifest with a wide range of signs and symptoms including neuropsychiatric problems, learning problems, communication issues and impaired motor function; they may also be accompanied by other congenital anomalies such as abnormalities of the heart, the skeleton, lungs, immune system and facial features.

Thousands of babies are born each year with a neurodevelopmental disorder and the global estimate for individuals with intellectual disability is 10.37/1,000 (1) and 62/10,000 (2) for autism. Neurodevelopmental delay is reported to affect 3-4% of children and young people.

Causes of neurodevelopmental delay

In the absence of birth trauma or other environmental causes, healthcare professionals often do not understand why a developmental disorder has occurred in an individual, which in turn means parents and families do not know why it has occurred, or whether it could happen again.

However, several studies in recent years have shown that many affected with these disorders do not develop normally because of an underlying error in their genes.

The genetic landscape of neurodevelopmental disorders

Only a few of the genetic forms of neurodevelopmental disorders are “common” or easily recognizable, such as trisomy 21 or Cornelia de Lange syndrome.

The vast majority are rare or ultra-rare and can be attributed to over 1,500 genetic loci (3,4). This extensive genetic heterogeneity presents a diagnostic challenge for even for the most experienced physician, as often each individual presents with a unique set of signs or symptoms (phenotype). Furthermore, the number of genes implicated in neurodevelopmental disorders is continuing to rise (5).

Therefore, the combination of the population prevalence and the complex genetic heterogeneity underlying neurodevelopmental disorders means that collectively they constitute a significant public health challenge for healthcare systems, and, for affected individuals and their families, this often means a long-protracted route to diagnosis.

Impact of diagnosing ultra-rare conditions

Whilst traditionally only a minority of families impacted by neurodevelopmental disabilities receive a confirmed diagnosis it can have a profound effect, enabling better care for the individual and informed counselling for the family about the risk of having another child.

Early detection of the underlying genetic cause can also facilitate more personalized therapies which may improve prognosis (6, 7) and as technology advances, knowledge of the causal gene and DNA variant can lead to deep understanding of the underlying biological cause of the disorder (8-11) which could ultimately result in novel new therapies and approaches (12).

The recent publication of the Medicines in Development for Cell and Gene Therapy Report indicates that there are 300 cell or gene therapies in development, 15 of which target genetic diseases.

Using genomics to diagnose neurodevelopmental disorders

Families affected by rare disorders, such as developmental disorders, often undergo a “diagnostic odyssey”, being seen by many healthcare professionals in different disciplines, receiving multiple misdiagnoses and taking years to receive a confirmed diagnosis and many individuals still remained undiagnosed.

However, advances in genomics analysis, particular exome sequencing, where all currently known genes can be examined simultaneously, have shown that the genetic cause of neurodevelopmental disorders can be identified in >40% affected individuals (5, 13-15)  

This revolution in genomics promises to transform clinical provision for neurodevelopmental disorders by providing rapid and accurate diagnoses and enabling tailored care provision, but until recently access to exome sequencing and data analysis technology was centralized and limited. Excitingly, this is no longer the case.

Centers without access to large in-house core sequencing facilities can now procure affordable exome sequencing from accredited commercial providers.

End-to end solutions for data processing, data analysis and clinical decision support are available to enable clinical and scientific experts to focus on diagnosing their own patients, an approach which has been demonstrated to improve diagnosis (27).

A recent case study in Cold Spring Harbor Molecular Case Studies from Dr Gholson Lyon and Dr Milen Velinov from the New York State Institute of Basic Research (IBR) illustrates the power of  this approach in the report of two siblings with ultra-rare VAC14 syndrome (16).

VAC14 syndrome study in Cold Springs Harbor Molecular Case Studies
Click the image to access the full case study

A gene agnostic phenotype driven approach

The consanguineous family in this study have six children, two of whom are affected with a rapidly progressive neurological disease with early childhood onset of severe progressive spastic paraparesis, learning difficulties and retinitis pigmentosa (RP).

The elder of the affected children was 21 years old when he was referred to the George A Jervis Diagnostic and Research Clinic at IBR, his similarly affected sister was four at evaluation.

Detailed clinical evaluation of the family was carried out including full clinical examination, family history, electroretinogram, brain magnetic resonance imaging (MRI), brain MR spectroscopy and review of previous tests.

Previous genetic tests failed to yield a diagnosis, including testing for Fragile X syndrome, PANK2, RPGR-ORF15 and chromosome microarray. Of note, brain MRI revealed abnormal magnetic susceptibility in two areas of the brain (globus pallidus and substantia nigra), similar findings are seen in a group of disorders characterized by neurodegeneration with brain iron accumulation (NBIA). Retinitis pigmentosa, as observed in the two affected family members, is not typical of the NBIA disorders.

Whole exome sequencing was carried out on the two affected siblings in 2016 and 2018.  Reanalysis of the data in 2018 was undertaken using a gene agnostic phenotype driven approach, utilizing variant prioritization algorithms such as Exomiser (in Congenica software) and wANNOVAR server.

These analyses ranked a homozygous missense variant (Val669Leu) in the VAC14 gene as the top gene variant. Segregation analysis was consistent and showed that only the two affected family members had two copies of the VAC14 Val669Leu variant.

VAC14 syndrome: an expanding phenotype?

VAC14 was first associated with autosomal recessive childhood-onset striatonigral degeneration (SNDC) in 2016 (17) and subsequently associated with autosomal recessive Yunis-Varón syndrome in 2017(18).

SNDC is a progressive neurological disorder that typically manifests around 18 months-3 years and is associated with overall regression, abnormal gait, specific brain abnormalities and other neurological symptoms, whereas Yunis-Varón syndrome presents in the neonatal period, includes profound developmental delay, skeletal anomalies, heart defects cataracts and structural brain abnormalities. Yunis-Varón syndrome can also be caused by mutations in the FIG4 gene.

VAC14 and FIG4 proteins form part of the same biological pathway and VAC14 has been shown to directly bind the FIG4, which is part of a complex process responsible for the synthesis of an important component of the cell membrane (phosphatidylinositol 3, 5-bisphosphate).

FIG4 is associated with a number of inherited neurological disorders, including Charcot Marie Tooth 4J. The VAC14 missense variant detected in the family presented in the case study (Val669Leu) affects part of the protein that binds FIG4 (19) and is involved in protein dimerization (20).

Whilst the clinical presentation of the young man in this case closely matches that of SNDC it is notable that retinitis pigmentosa (RP) has not previously been reported as a clinical phenotype associated with this disorder. To exclude other causes of RP the group screened the existing exome data for >90 genes associated with RP and no likely causal variants were identified.

Interestingly, in a recent publication outlining four additional families with variants in FIG4, one of the affected individuals was described as having an ocular dystrophy phenotype (bull’s eye maculopathy) (21).

Therefore, the group suggests the visual impairment with RP observed in this family may be associated with the VAC14 variant that segregates with the disorder in this family and that this may represent an expansion of the phenotypic associations for this ultra-rare disorder.

Halting a 21-year diagnostic odyssey

For the affected individuals, the parents and the wider family, genomic analysis has halted their 21-year diagnostic journey and provided them with a confirmed diagnosis of VAC14 syndrome. The parents can now be counselled accurately regards risk and reproductive choice, and the wider family can receive counselling and carrier testing as appropriate.

For the physicians who carried out this analysis and who care for rare disease patients like this family an accurate diagnosis can lead to changes in the patient care pathway, for example instigate changes in therapy, trigger participation in screening or advise on changes in educational and social provision (22).

For the research, clinical and patient community in general, case studies which share in depth descriptions of the manifesting symptoms of rare disease patients in the context of genomic findings can facilitate identification of other similarly affected families (23) a better understanding of the biological processes underlying the conditions (24) which in turn optimises the chances of development of targeted therapies.

For healthcare systems studies have shown that early diagnosis via genomic analysis can halt an expensive medical odyssey and provide significant system-wide savings, particularly in conditions which have a high a priori probability of a genetic cause, such as neurodevelopmental disorders. (23, 25-26).

The Institute for Basic Research in Developmental Disabilities (IBR)

The Institute for Basic Research in Developmental Disabilities (IBR) in New York opened its first laboratories in 1968 and at the time was the first large-scale institute in the world with the mandate to conduct basic and clinical research into the causes of neurodevelopmental disabilities. Today it provides the citizens of New York with a wholistic service for individuals and families impacted by developmental differences which encompasses provision of an integrated program of research, service, education and awareness raising.

This integrated approach is epitomized by the work of the George A Jervis Diagnostic and Research Clinic, a tertiary-level clinic that offers specialized diagnostic and consultative services for children, adolescents, and adults with developmental disabilities. The clinic enables the physicians and scientists at IBR to undertake clinical research in the field of developmental disabilities to try to determine the underlying causes and symptomology, to develop improved diagnostics, prevention and ultimately treatments.

Dr Milen Velinov and Dr Gholson Lyon lead the Department of Human Genetics and the Genomic Medicine laboratory at IBR and their work collectively focusses on the discovery, characterization and early recognition of the underlying genetic aetiology of neurodevelopmental disabilities.

Enabling the delivery of world class genomic medicine services

High quality clinical decision support platforms running secondary and tertiary pipelines, for sequencing alignment, variant calling and annotation, and data interpretation provide clinical and scientific experts, such as Dr Velinov and Dr Lyon, with the tools to be able to accurately and rapidly interrogate genomic data both for patient diagnosis and research.

The democratization of genomic medicine in turn leads to increased knowledge of the clinical presentation and underlying biology of ultra-rare disorders like VAC14 related syndromes.

Congenica is a clinical decision support tool designed to rapidly assess genomic data and provide healthcare professionals with answers that enable a fast and accurate diagnosis in rare and complex genetic diseases.

Find out more

Congenica is enabling genomic diagnoses in neurodevelopmental disorders. Discover how Congenica can help you increase your diagnostic confidence, diagnostic yield and workflow efficiency to save you time and improve patient outcomes.

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