Hearing Loss

oculo-auriculo-vertebral spectrum (OAVS) etiology

multifactorial/sporadic inheritance

SF3B2

OAVS common features

Mostly conductive HL (some mixed/SNHL)

Abnormality of 1st/2nd branchial arches (eyes,mouth, ear, maxilla, and mandible) → facial asymmetry/microsomia (on right side); microtia/anotia

Other organs: CNS, heart, kidneys, and skeletal

GJB2-related HL etiology

generally AR (but AD has variable HL and skin symptoms)

LOF

GJB2-related HL features

severe to profound non-progressive SNHL

GJB2-related HL testing

sequence analysis

STRC-related HL etiology

STRC and CATSPER2

AR

LOF

STRC-related HL common features

progressive, congenital, mild to moderate, bilateral, symmetric SNHL

decreased male fertility

STRC-related HL testing

CNV analysis

mito non-syndromic HL etiology

MT-TS1 (common variant: m.7445A>C/T/G)

MT-RNR1 (common variant: m.1555 A>G, m.1494 C>T)

maternal

MT-TS1: decrease in tRNASer(UCN)

MT-RNR1: alter suspectibility of ribosomes to aminoglycosides

mito non-syndromic HL common features

MT-TS1 (29%): childhood onset (generally non-syndromic) SNHL; palmoplantar keratoderma

MT-RNR1: SNHL; ototoxicity after admin of aminoglycoside antibiotic (gentamycin, amikacin)

mito non-syndromic HL testing

sequence analysis

CHD7-related disorder etiology

AD (de novo)

LOF

CHD7-related disorder common features

coloboma; heart defect; choanal atresia/stenosis; growth deficiency; DD/ID; genital hypoplasia; ear anomalies (short, wide ear w/ little or no lobe; "snipped-off" helix); hearing loss due to cranial nerve VIII hypo/a-plasia, ossicular malformations, and/or temporal bone abnormalities; CL/CP; clivus or cerebellar vermis hyopolasia

CHD7-related disorder testing

sequence analysis

Waardenburg syndrome eitology

WS1: PAX3

WS2: KITLG, MITF, SNAI2, SOX10

WS3: PAX3

WS4: EDN3, EDNRB, SOX10

WS1: AD

WS2: AD/AR

WS3: AD/AR

WS4: AD/AR

LOF

Waardenburg common features

WS1: congenital, bilateral, non-progressive, profound SNHL; (hypopigmentation) pigmentary changes of the iris, hair (<30), and skin w/ dystopia canthorum (telecanthus)

WS2: more SNHL and less pigmentary differences; no dystopia canthorum

WS3: SNHL, pigmentary abnormalities, upper limb anomalies like winged scapula, contractures, or syndactyly

WS4: SNHL, pigmentary abnormalities, Hirschsprung disease

Waardenburg syndrome testing

sequence analysis

Branchio-oto-renal spectrum disorder (BORSD) etiology

EYA1 (40%), SIX1 (2%), SIX5 (2.5%)

AD (>50% unknown cause)

LOF

Branchio-oto-renal spectrum disorder (BORSD) common features

second branchial arch anomalies (fistula or sinus tracts), conductive/SN/mixed HL; preauricular pits; auricular malformation; renal anomalies (kidney agenesis, hypo/dys-plasia); urinary tract anomalies (ureteropelvic junction obstruction)

Branchio-oto-renal spectrum disorder (BORSD) testing

sequence analysis

CdLS etiology

NIPBL (80%), RAD21, SMC3, BRD4, HDAC8 (4%), SMC1A (5%)

AD: NIPBL, RAD21, SMC3, BRD4

XL: HDAC8, SMC1A

(usually de novo)

NIPBL, RAD21, SMC3, BRD4, HDAC8: LOF variants

SMC3, SMC1A: GOF or dominant negative

CdLS common features

distinctive facial features (sonophrys, high arched/tick eyebrows, short nasal bridge, anteverted nares, small widely spaced teeth, and microcephaly), IUGR, hypertrichosis, upper limb reduction defects (subtle finger differences to oligodactyly); ID; ASD features; self-destructive tendencies; HL (>40% w/ SNHL); CHDs (pulmonic stenosis)

CdLS testing

sequence analysis

Usher syndrome etiology

Type 1: CDH23 (10-20%), CIB2, MYO7A (60-70%), PCDH15 (7-15%), USH1C (5-10%), and USH1G

Type 2: ADGRV1 (6.6-19%), USH2A (57-79%), and WHRN

Type 3: CLRN1

AR

LOF

Usher common features

First loss of night vision, then blind spots in peripheral, tunnel vision, may retain some central vision

Type 1: severe to profound SNHL, retinitis pigmentosa apparent in childhood; balance issues

Type 2: mild to severe HL affecting high frequencies; RP apparent in adolescence to adulthood; variable balance issues

Type 3: non-congenital HL starting in late childhood to adolescence which progresses to profound HL by middle age; RP apparent in late childhood to adolescence; usually no balance issues

Usher testing

sequence analysis

Jervell and Lange-Nielsen (JLNS) syndrome etiology

KCNQ1 (90%)

KCNE1 (<10%)

AR (but can lead to rare AD Long QT syndrome)

aberration in a potassium channel found in the stria vascularis of the cochlea (inner ear) and the heart

JLNS common features

congenital profound bilateral SNHL and long QTc interval that is usually associated w/ tachyarrhythmias

JLNS testing

sequence analysis

Pendred syndrome etiology

SLC26A4 (50%), FOX11, KCNJ10

AR

LOF → degeneration of sensor cells in cochlea

Pendred common features

congenital, severe to profound, SNHL; vestibular dysfunction (bilateral enlarged vestibular aqueduct (EVA) w/ or w/out cochlear (Mondini) hypoplasia); temporal bone abnormalities; euthyroid goiter

Pendred testing

sequence analysis

Alport syndrome etiology

COL4A5 (80-85%), COL4A3 (12-15%)

COL4A4

COL4A5: XL

COL4A3, COL4A4: AD/AR

Absence or underexpression of the collagen IV α3, α4, α5, and possibly α6 chains in the basement membrane such that the networks in epithelial or endothelial cells that they form are absent or defective

Alport common features

progressive renal disease; progressive (not congenital) SNHL present by late childhood or early adolescence; ocular findings (anterior lenticonus, maculopathy, corneal endothelial vesicles, recurrent corenal erosion); hematuria; proteinuria

XL: all males progress to ESRD and deafness and have risk for aneurysms of thoracic and abdominal aorta; females have later onset and more variability

AR: both males and females progress to ESRD and have juvenile onset HL

AD: slowly progressive ESRD and HL may not develop until later (dec. penetrance)

Alport testing

sequence analysis

Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) etiology

MT-TL1 (>80%) (common variant: m.3246 A>G), MT-ND5 (<10%)

maternal

LOF → impaired mito energy production, microvasculature angiopathy, and NO deficiency

MELAS common features

seizures; neurological regression (dementia like symptoms); muscle weakness; exercise intolerance; migraines w/ nausea and vomiting; cortical vision loss; HL (usually SN, mild but progressive); peripheral neuropathy; growth failure/short stature; stroke like episodes

MELAS testing

Sequence analysis via serial single-gene testing or multigene panel

muscle biopsy showing ragged red fibers (stained positively w/ cytochrome c oxidase stain)

lactic acidosis