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The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies
Author(s) -
Abu Diab Alaa,
AlTalbishi Ala'a,
Rosin Boris,
Kanaan Moien,
Kamal Lara,
Swaroop Anand,
Chowers Itay,
Banin Eyal,
Sharon Dror,
Khateb Samer
Publication year - 2019
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/aos.14095
Subject(s) - exome sequencing , medicine , retinal , exome , ophthalmology , genetics , mutation , biology , gene
Purpose To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses. Methods Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole‐exome sequencing ( WES ). Results Two affected subjects in family MOL 0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa ( RP ). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS 13B that is known to cause Cohen syndrome. The index case of family MOL 1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL 5, associated with nonsyndromic RP . The MOL 1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH 3A2 , reported to cause Sjögren‐Larsson syndrome ( SLS ). In the fourth family, SJ 002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns‐Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency‐20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS 2 . Conclusion Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRD s.