Application of Next-Generation–Sequencing to the Diagnosis of Genetic Disorders: A Brief Overview - Next Generation Sequencing Technologies in Medical Genetics - page 36

cardiomyopathy were found to have well-known disease mutations for HCM or
DCM. This approach allowed, for the fi rst time, a comprehensive genetic screening
in patients with hereditary DCM or HCM in a fast and cost-effi cient manner.
A different set of cardiomyopathies is caused by defects in primary electrical
conduction defects. The most common are the Brugada syndrome and Long QT
(LQT) syndrome. Mutations are seen in sodium and potassium channels. Brugada
syndrome is caused by mutations in eight genes ( CN5A , GPD1L , CACNA1C ,
CACNB2 , SCN1B , KCNE3 , SCN3B , and HCN4 ). LQT syndrome genes are labeled
LQT1 - 13 . NGS has tremendous potential in shortening the diagnostic odyssey in
these patients. In fact, several panels for these genes are commercially available by
a number of clinical laboratories nationwide. These NGS tests include a 12-gene
LQT syndrome panel, a nine-gene Brugada syndrome panel, and a 29-gene arrhyth-
mia panel that incorporates genes implicated in LQT syndrome, Brugada, catechol-
aminergic polymorphic ventricular tachycardia and several other arrhythmic
disorders, as well as sudden cardiac arrest.
Aortic root dilatations are another set of disorders for which NGS has already
established itself in a clinical setting. Aortic root dilatation can be caused by a num-
ber of disorders such as Marfan syndrome (MFS), Loeys-Dietz syndrome, Ehlers-
Danlos syndrome type IV, and congenital contractual arachnodactyly. In addition,
nonsyndromic causes of aortic root dilatation include mutations in genes related to
the structure and function of the aortic wall, including MYH11 , ACTA2 , SLC2A10 ,
and NOTCH1 . Commercial clinical laboratories offer a combination of any number
of these genes on their NGS panels. For example, the Marfan, aneurysm, and related
disorders NGS panel is a comprehensive gene sequencing test for ten genes ( ACTA2 ,
CBS , FBN1 , FBN2 , MYH11 , COL3A1 , SLC2A10 , SMAD3 , TGFBR1 , and TGFBR2 )
associated with MFS and MFS-related disorders.
Familial cholesterolemia is caused by mutations in LDLR gene, Apo-lipoprotein
B, and PCSK9 . Clinically, it is important to identify the proband's mutation so that
at-risk relatives can be recognized. Subsequently, at-risk individuals can be started
on cholesterol lowering medications, as dietary modifi cation will have no effect.
NGS offers a fast and effective way to diagnose predisposing mutations in these
disorders (Wooderchak-Donahue et al. 2012 ).

4.6 Ophthalmic Disorders

Mutations in more than 150 genes cause inherited retinal disorders, leading to a
diversity of overlapping phenotypes. These diseases may be stationary (i.e., con-
genital stationary night blindness) or progressive (i.e., retinitis pigmentosa). These
disorders may present by themselves, nonsyndromic, or as part of a syndromic dis-
order. To examine each individual gene is time-consuming and cost-prohibitive.
Audo et al. established a solution capture (Agilent SureSelect, SS) and Genome
Analyzer IIx (Illumina) approach to examine a 1,177 Mb region of interest against
254 known and candidate retinal disease genes (Audo et al. 2012 ). Their patients