Girisha KM Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal - 576 104 Email:girish.katta@manipal.edu
1 Exome sequencing as a diagnostic test in the clinic1,2
Since its first use nearly five years ago, next generation sequencing has made significant inroads into research as well as
diagnostic laboratories. Now here comes the proof for applying whole exome sequencing in the clinic for the diagnosis of
genetic disorders.1,2 Studies have shown that the diagnostic yield of exome sequencing is likely to be around 25%.
Compared with other traditional diagnostic tests, this yield is of immense value for physicians. The cost of the test
having come down significantly in the last two years, this is proving to be an important tool in the hands of
clinicians. If give it to an expert clinician along with a well-defined phenotype, the success is bound to be far
higher.
2 Another attempt to treat Duchenne muscular dystrophy3
Duchenne muscular dystrophy is a common genetic disorder and still lacks a specific curative therapy. Several
efforts in the past have failed and ongoing trials are yet to yield a tangible result that can be translated to
clinical practice. Wein and colleagues have demonstrated a truncated isoform generated by exon skipping
that protects muscle from contraction-induced injury and corrects muscle force to the same level as that
observed in control mice.3 To begin with, they have demonstrated that this particular isoform results from
usage of an internal ribosome entry site (IRES) within exon 5 in muscle from individuals with minimal
symptoms despite the presence of truncating mutations. There’s a long way to go, but several such efforts
are probably necessary before we have a permanent solution, that continues to elude both clinicians and
families.
We all know consanguinity increases the incidence of birth defects, but how does it affect the fetal outcome? A study by
Becker and colleagues has thrown light on this important aspect that we all face in our clinics routinely.4 After adjusting
for several factors, the incidence of congenital anomalies was found to be 2% for non-consanguineous couples versus 5.9%
for consanguineous couples (6.1% in first cousin progeny and 1.9% beyond first cousin) i.e. an excess of
3.9%. The authors have concluded that prevalence of major fetal anomalies associated with consanguinity is
higher than in evaluations based only on postnatal life, a message to take home for all those who marry a
relative!
We knew it, right? Many children with febrile seizures including MMR vaccine related febrile seizures have similar history
in a sib or a parent. Some preempt the attack by medications when MMR vaccine is given. Two papers now provide the
basis for these observations. Schubert and colleagues have shown that mutations in the STX1B gene explain autosomal
dominant fever associated epilepsy whereas Feenstra and colleagues have identified common genetic variants associated
with general and MMR vaccine–related febrile seizures.5,6
Susceptibility to infections is multifactorial and extremely rarely Mendelian. Dunstan and colleagues have identified
HLA-DRB1 as a genetic locus that has a role in susceptibility to enteric fever.7 Their study conducted in subjects from
Vietnam and Nepal, though lacking matched controls, implicates HLA-DRB1 as a major contributor to resistance against
enteric fever, presumably through antigen presentation.
References
1. Lee, H. et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312,
1880-7 (2014).
2. Yang, Y. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA312, 1870-9 (2014).
3. Wein, N. et al. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that
attenuates dystrophinopathy in humans and mice. Nat Med 20, 992-1000 (2014).
4. Becker, R. et al. Consanguinity and pregnancy outcomes in a multi-ethnic, metropolitan European
population. Prenat Diagn 35, 81-9 (2015).
5. Feenstra, B. et al. Common variants associated with general and MMR vaccine-related febrile seizures. NatGenet 46, 1274-82 (2014).
6. Schubert, J. et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy
syndromes. Nat Genet 46, 1327-32 (2014).
7. Dunstan, S.J. et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 46,
1333-6 (2014).
