The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

Alaa Abu Diab, Ala'a AlTalbishi, Boris Rosin, Moien Kanaan, Lara Kamal, Anand Swaroop, Itay Chowers, Eyal Banin, Dror Sharon*, Samer Khateb

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 MOL0760 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 VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 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 AGBL5, associated with nonsyndromic RP. The MOL1592 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 ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, 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 VARS2. 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 IRDs.

Original languageEnglish
Pages (from-to)e877-e886
JournalActa Ophthalmologica
Issue number6
StatePublished - 2019
Externally publishedYes


  • inherited rare disease
  • precise clinical diagnosis
  • syndromic retinal disease
  • whole-exome sequencing


Dive into the research topics of 'The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies'. Together they form a unique fingerprint.

Cite this