Paediatrics

The major focus of the Fetal Medicine sub-domain is the study of the genetic causes of fetal structural abnormalities (e.g. central nervous system anomalies, fetal hydrops, skeletal dysplasia, renal anomalies, cardiac anomalies) and severe early onset fetal growth restriction, in the absence of major fetal aneuploidies.

Prenatal diagnosis plays an essential role in contemporary obstetric care. Standard chromosome testing has been available since the 1960s and has been commonly used in the prenatal genetic testing when a fetus has abnormal findings on ultrasound. Quantitative fluorescence PCR and traditional karyotype have been the main means to detect fetal aneuploidies and other relatively larger translocations, deletions or duplications. However, these methods cannot identify microscopic and submicroscopic genomic imbalances. In recent years, there has been an introduction of genomic microarrays that provide a genome wide screen for genomic imbalances at a high resolution, allowing for the detection of microdeletion and microduplication syndromes. This is now the method of prenatal diagnosis when there are fetal structural abnormalities on an ultrasound scan as there is an additional diagnostic yield of up to 9% as compared to the traditional karyotype [1].

The diagnosis of many of the growth and endocrine disorders included in the 100k GP is based on clinical features and biochemical profile, but not on a precise molecular aetiology. Families want and seek precise genetic diagnoses so that they can fully understand what has happened and what may happen to their child. Over the last ~15 years, an increasing number of monogenic growth and endocrine disorders have been elucidated (including those identified by investigators in our sub-domain. What the 100k GP now offers is the opportunity to assign a specific genetic diagnosis to many more children with growth and endocrine disorders.
In addition functional work on genes causing growth and endocrine disorders has significantly extended our understanding of complex phenotypes (e.g. midline/eye abnormalities and the pituitary and relationships between systems (e.g. growth, cancer and metabolic predispositions. Within the 100k GP, functional work on novel growth & endocrine genes and novel variants in previously identified genes is very likely to help us to identify much broader spectra of phenotypes and enhance our ability to prognosticate in cases where families are desperate to know what lies ahead decade by decade.

The imprinting subdomain proposes genome analysis in patients with clinical imprinting disorders (ImpD), with emphasis on both coding and noncoding gene products, cis-acting distal or proximal regulatory sequences, cis-acting genomic rearrangements, and trans-acting mutations.
Currently, the clinical heterogeneity and epigenetic aetiology of ImpDs fragments existing clinical cohorts, hinders molecular diagnosis of ImpDs and impedes stratified care. Moreover, the phenotypes of ImpDs overlap with many existing recruitment categories (intellectual delay and abnormal behavior and growth disturbance).

The imprinting subdomain will, in conjunction with the 100,000 genomes project, seek externally funded collaborative funding for epigenetic analyses in order to identify undiagnosed ImpD patients within the 100K project. This will delineate an expanded phenotype of ImpD and enable effective translation of novel molecular diagnostic ImpD services into NHS practice.

Ciliopathies are incurable inherited diseases collectively affecting 1 per 200 births. A lack of formal clinical diagnostic measures, variable disease features and multiple organ involvement hamper clearcut clinical diagnosis, with patients subject to multiple clinic visits, delayed or missed diagnosis, and suboptimal disease management that impacts upon morbidity and lifespan. Mutations in >100 genes cause ciliopathies [2], with extensive genetic and phenotypic variability within and between different subtypes [3]. This large and complex disease spectrum of > 30 major subtypes has numerous disease variants that range from chronic diseases where lifelong disease management for better quality of life and survival is the priority, to lethal developmental malformations demanding better prenatal diagnosis options. Variable penetrance, epistatic alleles and triallelic inheritance are all proposed to influence ciliopathies, suggesting an extensive influence of modifier alleles [4-6]. Ciliopathies are a paradigm of rare disease complexity that promises to benefit from the GEL Project, addressing the unmet need of unrecognised ciliopathy patients, offering new cell biological clues and ideas for new gene-based therapeutics.

Numerous large-scale genome-wide genetic studies using both array-based and sequence-based technologies indicate that developmental disorders, as defined broadly above, represent a fundamental and uniquely informative domain of disorders for genetic research. These studies have demonstrated shared genetic aetiology across a broad range of frequently co-morbid neurodevelopmental disorders, such as intellectual disability (ID), autism and epilepsy. Moreover, the variable penetrance and expressivity of many multi-system disorders means that patients with identical mutations can have quite different clinical presentations. The proposed domain is ideal for conducting ‘in-the-round’ meta-analyses, e.g. of neurodevelopmental disorders, as well as sub-analyses of more specific disorders. Multi-system developmental disorders represent a major area of clinical need, with ID being the most frequently observed phenotype.