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

Abstract

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.

Keywords: inherited rare disease; precise clinical diagnosis; syndromic retinal disease; whole-exome sequencing.

Fig. 1.

Pedigrees of the included families. Affected subjects are indicated as black-filled objects, and genotype is written under the recruited subject symbol. Gray-filled shapes indicate patients with similar phenotype as detailed in the results section per anamnesis without examination. Arrows indicate index cases and deceased subject is indicated by oblique line.

Fig. 2.

Colour, autoflourescence (FAF) and optical coherence tomography (OCT) images of affected subjects. (A) MOL0760 IV:1 and MOL0760 IV:4 RE colour fundus photograph show normal looking optic disc, narrow retinal vessels and peripheral retinal atrophy. Corresponding FAF images show a hyper autoflourescent ring surrounding the fovea. SD-OCT horizontal cross sections demonstrate atrophy of the outer retinal layers while MOL0760 IV:4 present with cystoid macular oedema (CME). (B) BE ultra-wide field pseudocolour and FAF Optos photographs of MOL1514 III:1 show peripheral retinal atrophy encroaching the fovea combined with patches of pigmentation. SD-OCT horizontal sections show a preserved island of outer nuclear layers and ellipsoid zone within the fovea, complicated by CME. Retinal atrophy is surrounding the macula peripherally. (C) BE colour and near infrared reflectance photographs of MOL1592 II:1 show dot crystalline deposits within the macula with pigmentary changes, presented as hyperreflective dots along the inner nuclear layer and outer plexiform layers with preservation of the outer retinal layers.

Fig. 3.

Homozygosity mapping and Mutation Identification. (A) Homozygosity analysis of the recruited families. Homozygosity mapping of MOL0760 (HM-WES-MOL0760 IV:1, -IV:4 and -III:2 and SNP array HM-MOL0760 IV:1), MOL1592 II:1 and MOL1514 III:1. Data were analysed using the HomozygosityMapper server (Berlin, Germany [03/2016]): the x-axis represents the genomic location and y-axis represents the threshold for the Homozygosity score as a ratio over the maximum score. (B) Chromatograms of a homozygous affected individual (top), a heterozygous unaffected family member (bottom) in the families MOL760 (left) and MOL1514 (right). (C) Exome sequence alignment of the ALDH3A2 c.682C>T, p.(Arg228Cys) mutation region in MOL1592II:1. Only a representative set of reads is depicted.