EYA1 Deletion/Duplication (MLPA) Analysis for Branchio-Oto-Renal Syndrome Details
Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder with highly variable clinical manifestations involving branchial arch, otic, and renal anomalies. Two genes (EYA1 and SIX1) are known to be causative. The extreme variability of the disease, involving the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality, is seen not only among unrelated individuals, but also among individuals in the same family and even across the right and left sides in an affected individual.
Branchial arch anomalies include branchial fistulae and cysts and are found in 50-70% of individuals. Branchial fistulae appear as pin-point openings usually in the lower third of the neck. Branchial cysts appear as palpable masses, usually above the level of the hyoid bone.
BOR is estimated to account for 2% of profoundly deaf children. Hearing loss occurs in >90% of individuals diagnosed with BOR and may be conductive, sensorineural, or mixed, progressive or stable, and ranges from mild to severe in degree. Ear abnormalities can be found in the outer, middle, and inner ear. External ear abnormalities include preauricular pits/tags (>80%), auricular deformity, and atresia or stenosis of the external auditory canal. Middle ear abnormalities include malformation, malposition, dislocation, or fixation of the ossicles and reduction in size or malformation of the middle ear space. Inner ear abnormalities include cochlear hypoplasia, enlargement of the cochlear and vestibular aqueducts, and hypoplasia of the lateral semicircular canal. A temporal bone CT or MRI scan can be used to detect middle and inner ear abnormalities.Read More...
Renal anomalies occur in approximately two-thirds of individuals with BOR ranging from mild renal hypoplasia to bilateral renal agenesis, and may progress to end-stage renal disease (ESRD) later in life. Renal anomalies also include uretero-pelvic junction (UPJ) obstruction, calyceal cyst/diverticulum, calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux.
In the absence of a family history, three or more of the following major criteria OR two major and two minor criteria must be present to make the clinical diagnosis of Branchio-oto-renal (BOR) syndrome:
|Major Criteria||Minor Criteria|
|Second branchial arch anomalies||External auditory canal anomalies|
|Deafness||Middle ear anomalies|
|Preauricular pits||Inner ear anomalies|
|Auricular deformity||Preauricular tags|
|Renal anomalies||Other: facial asymmetry, palate abnormalities|
|EYA1||Eyes Absent 1||601653||8q13.3|
MLPA of the EYA1 gene is recommended for individuals with a diagnosis or suspicion of BOR, for whom sequencing of the EYA1 gene did not identify a pathogenic variant. Features of BOR can be variable, even within families, which should be considered in the medical evaluation and family history assessment of an individual. Approximately 40% of individuals with BOR will have pathogenic variants in the EYA1. Sequencing variants are more common, so reflexive testing from DNA sequencing to deletion/duplication analysis can be performed.
This test is performed by multiplex ligation-dependent probe amplification (MLPA) to detect the presence or absence of a deletion or duplication of one or more exons spanning the EYA1 gene.
Analytical and Clinical Sensitivity
This test is greater than 98% accurate in detecting single or multiple exon deletions and/or duplications at the analyzed loci. Pathogenic variants in the EYA1 gene are identified in ~40% of individuals with BOR syndrome. Up to 10% of individuals with BOR will have a chromosomal abnormality resulting in a deletion within the EYA1 gene.