lunes, 30 de junio de 2014

New testing guidelines for hearing loss support next-generation sequencing - Levenson - 2014 - American Journal of Medical Genetics Part A - Wiley Online Library

New testing guidelines for hearing loss support next-generation sequencing - Levenson - 2014 - American Journal of Medical Genetics Part A - Wiley Online Library

Birth Defects & Child Health

Updated guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend that clinicians consider next-generation sequencing (NGS) when testing for genetic causes of hearing loss.
The latest recommendations, which build on guidelines issued in 2002, include panel tests targeted at genes related to hearing loss, whole-exome sequencing (WES), and whole-genome sequencing (WGS) after negative results are returned on initial single-gene testing indicated by a patient's family medical history and presentation.
NGS may also be appropriate in cases that clinicians suspect are nonsyndromic and result from autosomal recessive inheritance, especially after negative results are returned on tests for mutations in the autosomal recessive DFNB1 locus for GJB2 or GJB6, according to recently published guidelines [Alford et al., 2014].
GJB2 and GJB6, which encode the proteins connexin 26 and connexin 30, respectively, account for the largest proportion of autosomal recessive early childhood hearing loss in many populations, the authors note.
The new guidelines come in response to published studies that look at causes of hearing loss across the genome and large panel-based genetic tests, says coauthor Heidi Rehm, PhD, Director of the Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts.

Steps to Take

Before any genetic testing is done, the ACMG recommends that clinicians complete a comprehensive evaluation of patients' medical and birth histories to help distinguish acquired versus inherited causes of hearing loss as well as perform audiology exams to determine the type and severity of hearing loss. If findings suggest syndromic genetic hearing loss, patients should be offered genetic counseling and genetic testing, which could include single-gene tests, panels, genomic sequencing, chromosome analysis, and microarray-based copy number analysis, based on clinical findings. If the hearing loss seems nonsyndromic and unrelated to an environmental cause, single-gene testing may be warranted if medical and family history or presentation suggest a particular etiology. If none is suggested, the next step could be GJB2 or GJB6 testing.
Figure 1. Audiology exams commonly used to detect hearing loss and clinical evaluations may soon be combined with more advanced testing methods including whole-exome sequencing.
If single-gene tests yield no diagnosis, clinicians may consider NGS, which is quickly replacing many single-gene tests for hearing loss and can assess patients whose phenotypes are not easily distinguished clinically, the guidelines note. NGS may be a cost-effective first- genetic test, the guidelines note.
However, the guidelines say little about what NGS technology to choose. “The technology is evolving so quickly,” explains Dr. Rehm, “so we can't say you must do a panel and then genomic sequencing or vice versa.”
The guidelines do, however, suggest testing issues to consider. For genomic sequencing, these include the likelihood of incidental findings and getting information that labs or practitioners cannot interpret, especially variants in genes that have yet to be associated with hearing loss or are unrelated to hearing loss. Likewise, WGS and WES may not read all regions of the genome and may miss certain deletions and duplications or copy number and structural variations.

Panel Tests

The guidelines recommend panel tests as good choices. “Once you get past connexin 26 [expressed by GJB2], there is no really common genetic cause. It's too expensive to test genes one by one,” Dr. Rehm adds. Currently, at least four U.S.- based labs, including hers, offer hearing loss panel tests.
However, the guidelines also point to drawbacks with panel tests. Those tests that use disease-targeted exon capture focused on specific genes may only sequence a subset of the genes known to cause hearing loss, and there is limited knowledge of which genes are involved in hearing loss.
Richard J.H. Smith, MD, Director of the Molecular Otolaryngology and Renal Research Laboratories at the Iowa Institute of Human Genetics at University of Iowa in Iowa City, is a proponent of panel testing for hearing loss. His lab offers a test that covers 90 genes known to cause hearing loss, which he suggests over any initial single-gene test.
Dr. Smith says because panel tests offer more depth of coverage in genes associated with hearing loss, they are superior to WES, which looks at 20,000 genes and may miss parts of them. “Each gene gets read more times with a panel [test],” says Dr. Smith. “There are no blank spots. There are always some blank spots with exome sequencing.”
Also new in the guidelines is a broader focus on diagnosing all causes of hearing loss, including pathogens and environmental factors, plus hearing loss with onset at all ages, says first author Raye Alford, PhD, Associate Professor in the Bobby R. Alford Department of Otolaryngology – Head and Neck Surgery at Baylor College of Medicine in Houston. Among these causes are noise exposure, congenital cytomegalovirus and rubella infections, premature birth, and mothers' use of certain drugs during pregnancy.
“Given the challenges that can exist in distinguishing between syndromic and nonsyndromic forms of hearing loss, all children and adolescents showing hearing loss without a known etiology, e.g., confirmed GJB2 mutations or documented congenital cytomegalovirus (CMV) infection, should be evaluated for syndromic conditions by a clinical geneticist,” the guidelines say.


  • Alford RLArnos KSFox MLin JWPalmer GCPandya ARehm HLRobin NHScott DAYoshinaga-Itano C2014ACMG Working Group on Update of Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss, for the American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee. Guideline for the clinical evaluation and etiologic diagnosis of hearing lossGenet Med 16(4):347355 PMID: 24651602.

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