IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Motile and non-motile cilia are critical to mammalian development and health. Assembly of these organelles depends on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). A series of human and mouse IFT74 variants were studied to understand the function of this IFT subunit. Humans missing exon 2, which codes for the first 40 residues, presented an unusual combination of ciliary chondrodysplasia and mucociliary clearance disorders while individuals carrying biallelic splice site variants developed a lethal skeletal chondrodysplasia. In mice, variants thought to remove all Ift74 function, completely block ciliary assembly and result in midgestational lethality. A mouse allele that removes the first 40 amino acids, analogous to the human exon 2 deletion, results in a motile cilia phenotype with mild skeletal abnormalities. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia could account for the motile cilia phenotype observed in human and mice.

The role of genetic counsellors in genomic healthcare in the United Kingdom: a statement by the Association of Genetic Nurses and Counsellors.

In the United Kingdom, genetic counsellors work together with clinical geneticists and clinical scientist colleagues within specialist genetics services, but they also often work in multidisciplinary teams (MDTs) outside of such services. There, they contribute genetic knowledge together with expert understanding of how to communicate genetic information effectively. They can offer education and support to the MDT, while providing management advice for both affected patients and the extended at-risk family members. As genomic technologies are implemented across many disciplines within healthcare, genetic counsellors are playing a key role in enabling non-genetic health professionals learn, understand and integrate genomic data into their practice. They are also involved in curriculum development, workforce planning, research, regulation and policy creation - all with the aim of ensuring a robust evidence base from which to practise, together with clear guidelines on what constitutes competence and good practice. The Association of Genetic Nurses and Counsellors (AGNC) in The United Kingdom (UK) and Republic of Ireland is committed to supporting genetic counsellors, across all sectors of healthcare and research, as they help deliver genomic medicine for the patient, family and world-class health services.European Journal of Human Genetics advance online publication, 22 March 2017; doi:10.1038/ejhg.2017.28.

What do nurses need to know about genetics?

This sixth article in our series on rare diseases explores the impact of a genetic diagnosis on patients and their families. As genomic testing becomes mainstream, practitioners need to understand the role of genetics in disease and know how to refer patients for help and advice.