Exome sequencing reveals <i><scp>ADAM</scp>9</i> mutations in a child with cone‐rod dystrophy

A paper in 2009 reported four families with cone-rod dystrophy (CORD, MIM#120970) due to loss of function mutations in ADAM9 (Parry et al. 2009); all affected individuals developed reduced visual acuity in the first decade of life. A further recent paper detailed a consanguinous family with early onset cone-rod dystrophy due to splice site mutations in ADAM9 (El-Haig et al. 2014). We report the detailed clinical phenotype in a child with retinal disease caused by a homozygous mutation in ADAM9. A male patient presented at age 3 years. He was noted in infancy to have a right convergent squint with poor vision and eccentric fixation. There was no nystagmus. He was otherwise well with normal development. The parents were from Pakistan and were first cousins. At last review, age 7, the vision was right 1.0 logMAR (Snellen 6/60), left 0.88 logMAR (Snellen 6/48) with a hyperopic, astigmatic refractive error of R + 4.00/−2.50 × 20 L + 4.00/−2.00 × 180. There was a moderate left divergent squint with eccentric fixation. Early posterior subcapsular cataract was noted. Fundus examination showed posterior pole atrophy with a white-speckled appearance, which extended to the arcades and encompassed the optic disc (Fig. 1). Retinal imaging demonstrated reduced autofluorescence in the posterior pole with atrophy of the outer retina on optical coherence tomography (Fig. 1). Pattern and flash electroretinography (PERG; ERG) performed at the age of 3 years using surface electrodes revealed an undetectable PERG and borderline photopic and scotopic ERGs. At the age of 7 years, the PERG and full-field ERG were performed using corneal electrodes to ISCEV standards. The PERG was undetectable in keeping with severe macular dysfunction, and mildly abnormal full-field ERGs were consistent with cone-rod dystrophy (Fig. 1). Whole exome sequencing was performed (AROS Applied Biotechnology, Aarhus, Denmark), which identified a novel, homozygous mutation in ADAM9, c.967delT; p.Ser323Glnfs*33, which on direct Sanger sequencing was shown to segregate in the family with both parents heterozygous for this mutation (Fig. 1). Non-syndromic, autosomal recessive CORD is rare and usually associated with biallelic mutations in ABCA4 (Bocquet et al. 2013). In the previous reports of CORD due to ADAM9, five families were identified with mutations leading to either aberrant splicing or premature truncation codons. Similar to our patient, all had poor vision in their first decade of life, no nystagmus and outer retinal atrophy of the macula. Most were also noted to have discrete white patches in the posterior pole and around the disc and a peripheral pigmentary retinopathy, which is not present in our patient. Retinal imaging in a previous report of the index family demonstrated posterior pole atrophy in two patients in their 40s with a similar appearance to our patient (Danciger et al. 2001). Electrophysiology in these two patients demonstrated severe loss of both cone and rod function. In the recent report of a single family, the youngest patient assessed was 17 years (El-Haig et al. 2014). Posterior pole atrophy was noted, and in the retinal images this also encompassed the disc. No electrophysiology was available. Given the young age of our patient, we have been able to demonstrate the electrophysiological phenotype of severe loss of macular function in the early stages with relatively mild peripheral retinal dysfunction. In both a canine and mouse model, there are cone and rod photoreceptor abnormalities on electrophysiology which are not apparent in very young animals but develop with time (Parry et al. 2009; Goldstein et al. 2010). In both models, histopathology localized the primary defect to the apical microvilli of the retinal pigment epithelium potentially mediated by failure of normal photoreceptor outer segment phagocytosis. These animal models show early preservation of photoreceptor structure despite dysfunction. This together with relatively good peripheral photoreceptor function in early human disease as illustrated by this case suggests that there is a therapeutic window for gene therapy in patients with mutations in ADAM9.

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