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Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

29 Jan, 15 | by hqqu

Learning outcomes

After completing this module you should be able to:

Be aware of the genetic heterogeneity of ID and the diagnostic yield of different approaches to investigation

Understand the challenges associated with interpreting variants identified by next generation sequencing (NGS) and the principles behind assigning causality

Understand the strengths and weaknesses of a targeted sequencing approach as compared to trio-exome analyses/ whole genome sequencing (WGS).

Written by:

Redin C, Gérard B, Lauer J, Herenger Y, Muller J, Quartier A, et al. (“Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders ”&page=1&locale=en_GB)


DCAF4, a novel gene associated with leucocyte telomere length

27 Jan, 15 | by hqqu

Leukocyte telomere length (LTL) is associated with a number of diseases. In particular, telomeres are short in patients with cardiovascular disease and long in patients with different types of cancer such as melanoma. In our study we identified a novel gene (DCAF4) associated with LTL in the general population. Our finding expands the spectrum of genes involved in the leukocyte telomere maintenance.

We also provided evidence that genes associated with LTL are enriched among genes engaged in melanoma in the general population. The model used in this research may be useful in testing the role of LTL genetics in other human cancers. (By Dr. Massimo Mangino, )

MuSK – a novel gene for fetal death

23 Jan, 15 | by hqqu

Fetal akinesia deformation sequence (FADS) is a broad spectrum of syndromes characterized by reduced or loss of fetal movement, arthrogryposis, intrauterine growth restriction and developmental abnormalities.

In this study, we identified a novel gene, MuSK (muscle-specific receptor tyrosine kinase), by whole exome sequencing in a Swedish family trio with fetuses affected by FADS. MuSK is important for the maintenance and development of the neuromuscular junction (NMJ) and the clinical phenotype of the fetuses described here is similar to many previously reported fetuses with mutations involved in the NMJ pathway. Present results can be used in prenatal screening or preimplantation genetic diagnosis when FADS associated with NMJ is suspected. (By Dr. Maria Wilbe, )Doc3


Mutation in RNF113A that shines a new light on trichothiodystrophy

22 Jan, 15 | by hqqu

The trichothiodystrophies (TTD) are characterised by brittle, sulphur deficient hair that has an unusual tiger-tail banding pattern under polarising light microscopy. People affected by TTD can experience a range of symptoms including dry skin, short stature, intellectual disability and susceptibility to infection. About half of the patients have an inability to properly repair DNA damage following exposure to ultra-violet (UV) light and this feature categorizes photosensitive and non-photosensitive forms of the disease. Initially described as a DNA repair syndrome, photosensitive TTD is now regarded as a transcription and repair syndrome. In contrast, very little is known about non-photosensitive TTD. We identified a mutation that affects the X-linked, RNF113A gene in two male cousins with TTD that do not have any problems with UV induced DNA repair. A new gene implicated in non-photosensitive TTD! The function of RNF113A is as yet unknown though similar proteins found in fish, flies and flat worms direct the formation of the brain and central nervous system suggesting a conserved role for this protein. (By Dr. Mark Corbett, )

Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1

22 Jan, 15 | by hqqu

Genetic changes of both NF1 genes are postulated to be necessary for the development of tibial pseudarthrosis in individuals with neurofibromatosis type 1 (NF1). However, the tissue origin of the “second hit” mutation remains unclear. Macro-sections of tibial pseudarthrosis tissue were exome sequenced, as well as a blood sample from a child with NF1. A splice site mutation was identified in the blood and tibial pseudarthrosis sample representing a germline mutation, while a somatic stop mutation was identified in just the tibial pseudarthrosis sample. The somatic mutation was enriched in the pseudarthrosis proliferative soft tissue, but absent in cortical bone. (By Dr. David Stevenson, )

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

21 Jan, 15 | by hqqu

Defects in complex IV of the respiratory chain may result in a variety of phenotypes and be caused by mutations in 20 genes, most of which are involved in assembly of the complex. Here, we have for the first time identified mutations in COA3 as a cause of complex IV deficiency in a patient with neuropathy, exercise intolerance, obesity and short stature. The mutations were identified by whole exome sequencing. COA3 encodes a protein that is involved in the early assembly of complex IV, and likely functions in a complex that stabilizes a COX1 assembly intermediate. (By Dr. Elsebet Ostergaard,

mirTrios: an integrated pipeline for detection of de novo and rare inherited mutations from trios-based next-generation sequencing

16 Jan, 15 | by hqqu

The rapid advances of Next-generation sequencing (NGS) technologies have greatly facilitated clinical genetic diagnosis of sporadic disease genome-widely. However, the vast amount of mutations generated by NGS poses multiple challenges for identification of functional mutations and candidate genes. We devolopped a web server named mirTrios to accurately detect de novo mutations (DNMs) based on Expectation-maximization (EM) model. In addition, to facilitate the interpretation of diverse mutations, mirTrios also surports identification of rare inherited mutations, known diagnostic variants, as well as the prioritization of novel and promising candidate genes. mirTrios provides an intuitive interface for the general geneticist and clinicians, which is freely available at (By Dr. Jinyu Wu, )

SeqHBase: a big data toolset for family-based sequencing data analysis

13 Jan, 15 | by hqqu

High-throughput sequencing technologies are now increasingly used to find disease genes, but it is difficult to infer biological insights from massive amounts of data in a short period of time. We developed a software framework called SeqHBase to help quickly identify disease genes. SeqHBase was developed based on Apache Hadoop and HBase infrastructure, which works through distributed and parallel manner over multiple data nodes. Its input includes coverage information of 3 billion sites, over 3 million variants and their associated functional annotations for each genome. With 20 data nodes, SeqHBase took about 5 seconds for analyzing whole-exome sequencing data for a family quartet and approximately 1 minute for analyzing whole-genome sequencing data for a 10-member family. We demonstrated SeqHBase’s high efficiency and scalability with several real sequencing data sets. (By Min He, Ph.D., )

The twisting tale of woolly hair: a trait with many causes

6 Jan, 15 | by hqqu

Woolly hair is a unique hair phenotype, which is characterized by extremely curly hair. While this type of hair is common in black people, it is extremely uncommon in non-blacks. When woolly hair appears together with thickening of the skin of the palms and soles, it should immediately raise the concern of Naxos or Carvajal syndromes, which are characterized by life-threatening cardiomyopathy, and should necessitate immediate referral to cardiac evaluation. The factors which control hair curliness are still obscure, but it is thanks to the recent discovery of the genes responsible for some of the woolly hair syndromes that these factors start to reveal. In this review we provide summary of the cell structures and factors which control woolly hair, and provide a unifying mechanistic pathway for the control of hair texture. Furthermore, this review provides an algorithm for directing the diagnosis of the patient with woolly hair. (By Dr. Yuval Ramot, )

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder

24 Dec, 14 | by hqqu

Mitochondria are energy making organelles within our cells. Iron-sulphur cluster assemblies (Fe-Sc) take part in the energy production within mitochondria. Problems during the Fe-Sc assembly or reduction in the amount of the assembly molecules may be damaging to brain cells such as myelin sheaths. Such damage may eventually cause degeneration in white matter in human brain and leads to neurodegenerative diseases. We investigated six patients with leukodytrophy from five unrelated families and discovered first disease-causing mutation in ISCA2, an essential molecule for maturation of mitochondrial Fe-Sc. The mutation seems an ancient one that was likely appeared around 4800 years ago. (By Dr. Namik Kaya, )

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