Rare disease research

In Europe rare diseases affect fewer than five in every 10,000 people. However collectively, rare conditions are not so rare, affecting a total of nearly 30 million in Europe alone. Children account for 50% of rare disease patients. At least 40% of these children don't have a diagnosis.

However, we know that more than 80% of rare diseases are caused by faulty genes. Insights from investigations of rare disease can also help improve understanding of more-common conditions.

Using genomic data and next generation technologies we are uncovering new genes for rare undiagnosed conditions. Each one of these provides an opportunity to stitch together disease mechanisms. Importantly, our discoveries will allow a precise genetic diagnosis for a greater number of children affected by the conditions we are investigating, and help inform better clinical management.

A crucial component of success in rare-disease research is establishing strong connections with doctors and the patient community. Therefore, we are also very interested in biobanks and registries of rare diseases which we can collaboratively participate with. We also routinely share our knowledge of genotype-phenotype on databases such as ClinVar to aid the wider medical genetics community.

We are assembling a database of the mutations we have identified, and the conditions associated with them. The database can be found here:



Through collaborations we are investigating a variety of Mendelian diseases in order to identify the underlying genetic cause. The study cohort of individuals have undergone whole-exome sequencing and genetic analysis has already successfully identified many mutations in known genes, as well as novel genes not previously attributed to a phenotype.

Many of the parents in the recruited study are consanguineous (have a high degree of relatedness), and therefore offspring have elevated stretches of homozygosity. The autozygous stretches within their genome often harbour loss of function (LoF) mutations which lead to complete inactivation or dysfunction of genes. Studying consanguineous offspring with clinical phenotypes has been shown to be very useful for identifying disease causal mutations, and the population as a whole can speed up the characterisation of novel gene functions as well as indicating nonessential genes and/or regions in the human genome.

We are currently assembling a database of genetic variation identified in the cohort, and for the data from participants that have consented to general data sharing this will be made available to the scientific community upon request.

This is an example of a pedigree (a graphical representation of a family history), showing the members of the family that are affected by the disease (LEFT). The image on the right shows a change in the DNA sequence that results in a faulty protein associated with the disease.

This is an example of a pedigree (a graphical representation of a family history), showing the members of the family that are affected by the disease (LEFT). The image on the right shows a change in the DNA sequence that results in a faulty protein associated with the disease.


Arrhythmias (abnormal heart rhythms) are experienced by more than 2 million people a year in the UK. The heart's rhythm is controlled by electrical signals. It may beat too slowly, too quickly, or irregularly. Most people with an abnormal heart rhythm can lead a normal life if it is properly diagnosed.

Some people however are affected by rare inherited arrhythmias such as Long QT syndrome (LQTS), or Brugada Syndrome (BrS), which can cause fainting or fits (seizures), and can be associated with an increased risk of sudden death. We are interested in understanding the role of common and rare variants in determining risk of these conditions.



Behr ER, Savio-Galimberti E, Barc J, Holst AG, Petropoulou E^, Prins BP, Jabbari J, Torchio M, Berthet M, Mizusawa Y, Yang T, Nannenberg EA, Dagradi F, Weeke P, Bastiaenan R, Ackerman MJ, Haunso S, Leenhardt A, Kääb S, Probst V, Redon R, Sharma S, Wilde A, Tfelt-Hansen J, Schwartz P, Roden DM, Bezzina CR, Olesen M, Darbar D, Guicheney P, Crotti L; UK10K Consortium, Jamshidi YRole of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc Res. 2015 Jun 1;106(3):520-9.

Behr ER, Ritchie MD, Tanaka T, Kääb S, Crawford DC, Nicoletti P, Floratos A, Sinner MF, Kannankeril PJ, Wilde AA, Bezzina CR, Schulze-Bahr E, Zumhagen S, Guicheney P, Bishopric NH, Marshall V, Shakir S, Dalageorgou C^, Bevan S, Jamshidi Y, Bastiaenen R, Myerburg RJ, Schott JJ, Camm AJ, Steinbeck G, Norris K, Altman RB, Tatonetti NP, Jeffery S, Kubo M, Nakamura Y, Shen Y, George AL Jr, Roden DM. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. PLoS One. 2013 Nov 6;8(11):e78511.

Jamshidi Y, Nolte IM, Dalageorgou C^, Zheng D, Johnson T, Bastiaenen R, Ruddy S, Talbott D^^, Norris KJ, Snieder H, George AL, Marshall V, Shakir S, Kannankeril PJ, Munroe PB, Camm AJ, Jeffery S, Roden DM, Behr ER. Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. J Am Coll Cardiol. 2012 Aug 28;60(9):841-50.

Kääb S, Crawford DC, Sinner MF, Behr ER, Kannankeril PJ, Wilde AA, Bezzina CR, Schulze-Bahr E, Guicheney P, Bishopric NH, Myerburg RJ, Schott JJ, Pfeufer A, Beckmann BM, Martens E, Zhang T, Stallmeyer B, Zumhagen S, Denjoy I, Bardai A, Van Gelder IC, Jamshidi Y, Dalageorgou C^, Marshall V, Jeffery S, Shakir S, Camm AJ, Steinbeck G, Perz S, Lichtner P, Meitinger T, Peters A, Wichmann HE, Ingram C, Bradford Y, Carter S, Norris K, Ritchie MD, George AL Jr, Roden DM. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circ Cardiovasc Genet. 2012 Feb 1;5(1):91-9.



Cardiomyopathy is a disease of the heart muscle which affects its size, shape, structure and function. Common cardiomyopathies include hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The condition is often inherited, and in some cases is associated with an increased risk of sudden cardiac death (SCD). We know that changes in the DNA sequence of certain genes cause many of the cases of cardiomyopathy, however in at least 40% of individuals with this condition the gene affected is not known. We are therefore using Next Generation Sequencing technology to try and identify the DNA changes in families without a genetic diagnosis. As the genes are often novel (i.e. they haven't been linked to this condition before), finding a variant is only the first step in proving it is the cause.


Edward G. Jones, Neda Mazaheri, Reza Maroofian, Mina Zamani, Tahereh Seifi, Alireza Sedaghat, Gholamreza Shariati, Yalda Jamshidi, Hugh D. Allen, Xander H. T. Wehrens, Hamid Galehdari & Andrew P. Landstrom. Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy. Scientific Reports volume 9, Article number: 9038 (2019). Link to article.

Hedberg-Oldfors C, Abramsson A, Osborn DPS, Danielsson O, Fazlinezhad A, Nilipour Y, Hübbert L, Nennesmo I, Visuttijai K, Bharj J^, Petropoulou E^, Shoreim A^, Vona B, Ahangari N, Dávila López M, Doosti M, Banote RK, Maroofian R^, Edling M, Taherpour M, Zetterberg H, Karimiani EG, Oldfors A, Jamshidi Y. Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Human Molecular Genetics, 01 February 2019. Full text link.

Petropoulou E, Soltani M, Firoozabadi AD, Namayandeh SM, Crockford J, Maroofian R, Jamshidi YDigenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy. Eur J Med Genet. 2017 Sep;60(9):485-488.

Muggenthaler M, Petropoulou E^, Omer S, Simpson MA, Sahak H, Rice A, Raju H, Conti FJ, Bridges LR, Anderson LJ, Sharma S, Behr ER, Jamshidi YWhole exome sequence analysis reveals a homozygous mutation in PNPLA2 as the cause of severe dilated cardiomyopathy secondary to neutral lipid storage disease. Int J Cardiol. 2016 May 1;210:41-4.



Congenital muscular dystrophy (CMD) is a term used for a group of genetic muscle-wasting conditions, in which the symptoms become apparent at an early age. They cause muscles to weaken and waste over time, leading to increasing disability. They can also cause learning difficulties.


Muto V, Flex E, Kupchinsky Z, Primiano G, Galehdari H, Dehghani M, Cecchetti S, Carpentieri G, Rizza T, Mazaheri N, Sedaghat A, Vahidi Mehrjardi MY, Traversa A, Di Nottia M, Kousi MM, Jamshidi Y, Ciolfi A, Caputo V, Malamiri RA, Pantaleoni F, Martinelli S, Jeffries AR, Zeighami J, Sherafat A, Di Giuda D, Shariati GR, Carrozzo R, Katsanis N, Maroofian R, Servidei S, Tartaglia M. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology. 2018 Jul 24;91(4):e319-e330.

Maroofian R, Riemersma M, Jae LT, Zhianabed N, Willemsen MH, Wissink-Lindhout WM, Willemsen MA, de Brouwer APM, Mehrjardi MYV, Ashrafi MR, Kusters B, Kleefstra T, Jamshidi Y, Nasseri M, Pfundt R, Brummelkamp TR, Abbaszadegan MR, Lefeber DJ, van Bokhoven H. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.Genome Med. 2017 Dec 22;9(1):118.

Osborn DPS, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y*, Manzini MC*. Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy. Am J Hum Genet. 2017 Mar 2;100(3):537-545.