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Home , Genetic disorder, Usher syndrome

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Assessment of genetic disorders: congenital sensorineural loss

BY EMMA CLEMENT AND MARIA BITNER-GLINDZICZ

evere or profound inherited hearing impairment, which specifically about consanguinity and sensorineural hearing may be either syndromic or non- ethnicity are important. A history of impairment (SNHI) is a syndromic. consanguinity may suggest recessive Scommon , affecting inheritance and homozygosity for a approximately 1 in 1000 newborns [1]. Syndromic hearing particular . Some SNHI may result from environmental impairment are particularly prevalent in certain causes or have a genetic basis. Syndromic HI accounts for ethnic groups and may be screened The genetic causes can be further approximately 30% of genetic SNHI. for quickly. Other relevant questions subdivided into non-syndromic There are several hundred (mostly include antenatal and birth history, (isolated HI) or syndromic, where rare) reported syndromes associated developmental milestones (delayed the HI forms part of a more complex with SNHI; some of the more common walking is often seen with vestibular medical disorder. or diagnostically important ones are involvement), personal or family history The is encoded summarised in Table 2 [4]. of renal ( as DNA sequences packaged into Establishing a syndromic genetic and Branchio-oto-renal syndrome) or the 23 pairs of and diagnosis is important for several ophthalmological involvement (Usher mitochondrial DNA. A reasons: syndrome, and can be defined as a condition caused • There may be surveillance ). A full examination by a pathological alteration in the implications to consider such as should be performed including a genome. Variation in the genome is monitoring for thyroid dysfunction detailed inspection of the ears, skin and normal and usually not detrimental. in , or renal associated structures. Some alterations do lead to clinical dysfunction in branchio-oto-renal problems, usually as a result of syndrome Investigations abnormal expression of the (s) • It may inform management These should be tailored to the history; encoded by the affected (s). This decisions regarding the benefit or for a good review see [5]. Often non- can in turn cause abnormal growth otherwise of . genetic investigations may give clues as and development and sometimes the Patients with for to an underlying aetiology and may help outcome is a recognisable genetic example may lose vision direct subsequent genetic tests. These disorder. A genetic disorder may be and therefore lose the ability to include: inherited or occur sporadically, due to communicate by sign language, • Audiograms in patient and parents. new mutations. so early bilateral cochlear These may indicate an inheritance Genetic alterations can occur at implantation is important pattern or be typical for a particular several levels, summarised in Table 1. • It may suggest other preventative disorder (‘ski-slope’ audiogram measures such as the avoidance appearance in TMPRSS3 associated Non-syndromic hearing of aminoglycosides in some cases HI, or low frequency non-syndromic impairment of mitochondrial HI HI seen as a result of mutation There are over 100 known loci for non- • It allows accurate genetic of WFS1). They should be sent with syndromic SNHI and more remain to counselling and estimation of referral where possible be discovered. This includes autosomal recurrence risk in a family, which • CMV testing in order to exclude a dominant, autosomal recessive and is important to parents. common environmental cause of HI X-linked variants [2]. Mutation in GJB2 • Imaging of the (enlarged (encoding the protein 26) is Assessment of a child vestibular aqueducts in Pendred by far the most common genetic cause presenting to with syndrome, absent semicircular of non-syndromic SNHI and accounts canals in CHARGE syndrome) for up to 50% of recessive cases in • Urinalysis for haematuria in Alport syndrome some populations [3]. GJB2 associated History and examination • review (in all cases SNHI is usually congenital and is As with all specialities, the assessment to correct but also frequently detected by the Newborn of a patient in the genetics service to examine for Hearing Screening programme. It is consists of taking a good history and in established Usher syndrome and most commonly seen as an autosomal examination. In addition, drawing a retinal detachment in Norrie recessive trait, although a few specific, three generation pedigree and enquiring rare mutations may cause dominantly disease)

ent and audiology news | NOVEMBER/DECEMBER 2014 | VOL 23 NO 5 | www.entandaudiologynews.com ENT FEATURE

TABLE 1: MECHANISMS OF GENETIC DISEASE AND TESTING OVERVIEW

Genetic alteration Definition Example Investigation Chromosomal disorder Whole or part of a Karyotype or Microarray is missing or duplicated, large enough (Trisomy 21) (see Box 1) to be seen by standard karyotype. Microdeletion or Part of a chromosome is missing or 10p14 microdeletion syndrome FISH (fluorescent in situ Microduplicaton duplicated. including the GATA3 gene hybridisation) May be too small to be seen on 1p36 Microarray karyotype. Single gene disorders Mutation of a single gene. GJB2 (usually AR) Direct gene testing Inheritance may be autosomal Stickler syndrome (AD) dominant, autosomal recessive or Usher syndrome (AR) x-linked. Norrie syndrome (XL) Mitochondrial Maternally inherited. m.1555A>G (HI associated with Direct testing Often multisystemic features. aminoglycoside exposure) m.3243A>G (associated with maternally inherited and ) AD: autosomal dominant, AR: autosomal recessive, XL: X-linked, HI: hearing impairment.

TABLE 2: SYNDROMIC FORMS OF HEARING IMPAIRMENT

Condition Clinical Features Inheritance Gene(s)

Pendred syndrome Most common form of syndromic deafness AR SLC26A4 EVA Thyroid dysfunction

Usher syndrome Three subtypes with molecular heterogeneity AR Includes: All have HI and progressive RP MYO7A, USH1C, Vestibular function may be affected CDH23, USH2A, CLRN1 and others

Waardenburg syndrome Four subtypes with molecular heterogeneity AD (type 1-3) Includes: All have HI associated with pigmentary AR (type 4) PAX3, MITF, SNAI2, abnormalities of skin, eyes and hair EDNRB

Jervell and Lange Congenital profound SNHI AR KCNQ1, Neilsen Absent vestibular function KCNE1 Long QT syndrome

Alport syndrome Progressive high frequency HI X-linked COL4A5, Glomerulonephritis AR COL4A3, COL4A4

Branchio-oto-renal (BOR) Preauricular ear pits AD EYA1, SIX1, SIX5 Pinna abnormalities Branchial pits and sinuses Renal hypoplasia/dysplasia

Stickler syndrome High frequency HI AD Includes: Cleft palate COL2A, COL11A1, Mid-face hypoplasia COL11A2 High myopia and retinal detachment arthropathy

HI: Hearing Impairment, EVA: Enlarged Vestibular Aqueducts, RP: Retinitis Pigmentosa, AR: Autosomal Recessive, AD: Autosomal Dominant.

ent and audiology news | NOVEMBER/DECEMBER 2014 | VOL 23 NO 5 | www.entandaudiologynews.com ENT FEATURE

Box 1: What is a microarray? “Often non-genetic

A microarray, in simple terms, is a detailed chromosome test. Rather than looking investigations may through the microscope at the structure and banding pattern of chromosomes give clues as to an as would a conventional karyotype, a microarray analyses for the presence or absence of thousands of different areas of the genome, looking to detect missing underlying aetiology.” or duplicated regions. This allows one to pinpoint areas of deletion or duplica- tion on chromosomes. A microarray may detect aberrations as small as 0.1Mb (100,000 bases) whilst a karyotype would only detect much larger changes ~10Mb (10,000,000 bases). Microarray testing will not detect alterations in single , a directed gene test is required for this. Microarray testing has now largely

superseded karyotyping as a first line genetic investigation. References 1. Fortnum HM, Summerfield AQ, Marshall DH, et al. Prevalence of permanent childhood hearing impairment in the United Kingdom and implications for universal neonatal hearing screening: questionnaire based ascertainment Box 2: Next generation sequencing and sequencing. study. BMJ 2001;323(7312):536-40. 2. Hereditary hearing loss. Historically, establishing a genetic diagnosis in an individual has meant targeted http://hereditaryhearingloss.org Last accessed ‘Sanger’ sequencing of a . Sanger sequencing is however time September 2014. consuming and costly and there are many genes involved in HI. As a result, it has 3. Gasparini P, Rabionet R, Barbujani G, et al. High carrier frequency of the 35delG deafness not been practically possible to sequence large numbers of genes in an individ- mutation in European populations. Genetic ual and many patients have remained without genetic confirmation of their con- Analysis Consortium of GJB2 35delG. Eur J Hum Genet 2000;8(1):19-23. dition. Next generation sequencing (NGS) technology allows high-throughput 4. London Medical Database. testing and has increased sequencing capacity vastly. This has in turn reduced http://www.lmdatabases.com Last accessed September 2014. the cost of sequencing, enabling new diagnostic approaches. This may be in the 5. Ardle BM, Bitner-Glindzicz M. Investigation of form of a ‘gene panel’, where a number of known HI genes are sequenced in the child with permanent hearing impairment. parallel rather than sequentially. This approach has been shown to improve diag- Arch Dis Child Educ Pract Ed 2010;95(1):14-23. nostic rates in HI [6]. NGS also facilitates ‘’, where all the cod- 6. Shearer AE, Black-Ziegelbein EA, Hildebrand MS, et al. Advancing for ing exons in a genome are sequenced. This approach may detect a pathogenic deafness with genomic technology. J Med Genet mutation in a gene not previously associated with SNHI [7]. This technology is 2013;50(9):627-34. 7. Diaz-Horta O, Duman D, Foster J 2nd, et al. relatively new and requires expertise in bioinformatics interpretation, however it Whole-exome sequencing efficiently detects promises to vastly improve diagnostic capacity. rare mutations in autosomal recessive nonsyndromic hearing loss. PLoS One 2012;7(11):e50628.

• Vestibular assessment if motor The last few years have seen huge delay is a feature. Confirmed advances in genetic technology and vestibular involvement should have paved the way for new diagnostic prompt: approaches in clinical genetics. These º ECG (Jervell and Lange-Nielsen are now starting to filter through into Emma Clement, syndrome) clinical practice and have the potential Specialist Registrar in Clinical Genetics, º Electroretinogram to hugely improve diagnostic rates. Of Great Ormond Street (Usher syndrome) particular note is the development of Hospital º MRI / CT scan of the inner ear. specialised gene panel tests and the NHS Foundation Trust, advent of exome sequencing (Box 2). Great Ormond Street, London, WC1N 3JH, UK. Genetic investigations Exome sequencing refers to sequencing In order to arrange the appropriate of all of the protein-coding ‘exons’ in investigations a basic knowledge of the the genome. Although not yet widely Declaration of different types of genetic disorder and available on a routine basis, both are competing interests associated testing is required (Table 1). increasingly forming part of clinical None declared In practice, an individual presenting genetic practice. Maria with non-syndromic congenital or Bitner-Glindzicz, childhood-onset HI will usually have Conclusion GJB2 screened at an early stage. If there Professor of Clinical and Consideration of a genetic aetiology Molecular Genetics, are additional features that clearly should form part of the routine UCL Institute of point to a specific cause, targeted evaluation of an individual with HI, Child and Great Ormond Street gene testing may be appropriate with or without a family history and Hospital (e.g. pigmentary abnormalities in can positively impact management NHS Foundation Trust, ). A child strategies for the patient and other Great Ormond Street, London, WC1N 3JH, UK. with HI and dysmorphic features family members. Referral to clinical Declaration of may have a microarray to exclude a genetics service may be beneficial in competing interests E: maria.bitner@ None declared ucl.ac.uk microduplication or microdeletion cases where there is a family history of (Box 1). HI or where a syndromic cause is likely.

ent and audiology news | NOVEMBER/DECEMBER 2014 | VOL 23 NO 5 | www.entandaudiologynews.com