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The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy
  1. Inam N Bifari1,
  2. Sahar M Elkhamary2,
  3. Hanno J Bolz3,4,
  4. Arif O Khan1
  1. 1Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  2. 2Division of Radiology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  3. 3Center for Human Genetics, Bioscientia, Ingelheim, Germany
  4. 4Institute of Human Genetics, University of Cologne, Cologne, Germany
  1. Correspondence to Dr Arif O Khan, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia; arif.khan{at}


Background Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140). Most studies have focused on syndromic features and are by non-ophthalmologists. We highlight the ophthalmic phenotype.

Methods Retrospective consecutive case series (2010–2014).

Results Twelve subjects with confirmed homozygous mutations were identified (11 consanguineous families; 7 boys; assessed at age 10 months to 20 years, average and median age 6.5 and 4 years). All were homozygous for the same IFT140 mutation (c.1990G>A; p.Glu664Lys) except one who was homozygous for c.1541_1542delinsAA. All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception. In early childhood, nine were noted to stare at lights, four were noted to have a happy demeanour, high hyperopia was typical, and electroretinography was non-recordable. Fundus appearance was grossly normal before the age of 1 year but thereafter appeared dystrophic. Eight children had developmental delay, two had short stubby fingers, and one had renal disease, but four had no evident extraocular disease, including one aged 18 years who also had two older affected siblings in their twenties who remained non-syndromic and were excelling academically.

Conclusions Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia. Developmental delay is common but not universal and not all patients have obvious extraocular findings. The c.1990G>A mutation represents a founder effect or mutational hotspot on the Arabian Peninsula.

  • Child health (paediatrics)
  • Dystrophy
  • Genetics
  • Retina
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Ciliopathies are a category of disease due to impaired function of cilia, evolutionarily highly conserved hair-like organelles found in virtually all eukaryotic cells.1 There are two basic types of cilia—motile cilia, found in certain organs such as the respiratory tract or reproductive system, and primary cilia, which are present in virtually all vertebrate cells, functioning as cell sensors that relay information from the external environment during/after development (eg, guiding skeletal development) or between two compartments of the same cell (eg, between the inner and outer segments of the photoreceptor cell).1 Most ciliopathies are related to mutations in genes that have roles in primary cilia. Ciliopathies can be organ-specific, such as polycystic kidney disease or Leber congenital amaurosis, or can be syndromic, such as Bardet-Biedl or Alström syndrome.2 Sometimes children with syndromic ciliopathy can initially be thought to have only isolated Leber congenital amaurosis, before systemic manifestation becomes evident.3 ,4 The primary cilium complex involves hundreds of proteins, and the number of recognised ciliary genes and ciliopathy phenotypes continues to expand.

Intraflagellar transport protein 140 Chlamydomonas homologue (On-line Mendelian Inheritance in Man (MIM) *614620, IFT140) encodes a component of the ciliary intraflagellar transport complex A (IFT-A), which is involved in retrograde ciliary transport. Mutations in genes responsible for IFT-A cause the conorenal syndromes Mainzer-Saldino syndrome (MIM #266920) and, less commonly, Jeune syndrome (MIM %208500).5 ,6 Mainzer-Saldino syndrome is characterised by phalangeal cone-shaped epiphyses, chronic renal disease, early-onset retinal dystrophy, and developmental delay. Occasional features include short stature, cerebellar ataxia, and hepatic fibrosis. Jeune syndrome phenotypically overlaps with Mainzer-Saldino syndrome and has more than one recognised genetic cause. Jeune syndrome is characterised by cone-shaped epiphyses, shortened ribs and a narrow chest, and short stature. Additional features include a variety of findings common to systemic ciliopathies such as renal disease, retinal dystrophy, pancreatic cysts, hepatic fibrosis, and developmental delay.

To date, 15 families with biallelic IFT140 mutations have been reported in the literature, the majority of which had obvious syndromic phenotypes.3 ,5 ,6 However, with the exception of two children from two Saudi families who we previously reported,3 the presenting ophthalmic phenotype of children with IFT140-related retinopathy has not been well characterised. The purpose of this report is to highlight ophthalmic features in a cohort of Saudi children referred to a paediatric ophthalmologist for low vision and found to harbour recessive IFT140 mutations.


Institutional board approval was obtained for this report, part of a retrospective review of early-childhood onset retinal dystrophies referred to a paediatric ophthalmologist (AOK). This retrospective consecutive case series (2010–2014) includes children referred for low vision, confirmed to have early childhood onset retinal dysfunction, and found to harbour recessive mutations in IFT140. Electroretinography (ERG) was done using standards of the International Society of Clinical Electrophysiology of Vision;7 chloral hydrate sedation was used for children 1–4 years old. General medical history was recorded, with specific questioning regarding the presence or absence of the following: neurodevelopmental delay, deafness, polydactyly, heart disease, kidney malformation, skeletal disease and obesity. Neurodevelopmental delay was defined as delayed speech, socialisation, and/or major motor landmarks by age 2 years.8

All subjects who had genetic testing underwent next-generation sequencing of a panel of all known retinal dystrophy genes (known by the end of 2013 or 2014, depending upon when they attended the clinic) with confirmatory Sanger sequencing using previously described methods9 except for subject 8, who underwent direct IFT140 sequencing. Bioinformatic programmes were used for evaluation of variants’ pathogenicity as previously described.9 ,10 After next-generation sequencing, verification of identified variants and segregation analyses were carried out by polymerase chain reaction amplification of the corresponding exon, followed by Sanger sequencing.


Eleven probands (12 affected subjects; 7 male) were identified, two of whom were previously reported.3 All harboured the same homozygous IFT140 mutation (c.1990G>A; p.Glu664Lys) except one (c.1541_1542delinsAA in subject 10). There were no additional suspicious variants in other tested genes on the next-generation gene panel except in subject 10a, who was a heterozygous carrier for a nonsense mutation (c.1189C>T, p.Gln397*) in ABHD12 (MIM *613599; NM_001042472.2) and a complete deletion of NPHP1 (MIM *607100). The complete deletion of the NPHP1 gene was confirmed by multiplex ligation-dependent probe amplification, which also confirmed heterozygosity.

All subjects had infantile nystagmus and poor vision noted since birth. Best recorded visual acuity was hand motion or light perception. Eight subjects had developmental delay. Four subjects were clinically normal other than their retinal dystrophy at the time of last assessment (aged 10 months to 20 years). During infancy, nine were noted to stare at lights and four were noted to have a happy demeanour. All were hyperopic at the time of cycloplegic refraction except one older subject, who had keratoconus. All subjects who had hand X-rays had phalangeal cone-shaped epiphyses. Further details are provided in table 1, which also includes information regarding five additional clinically affected relatives (from two families) who did not undergo genetic testing. The fundus appeared grossly normal in children under 1 year old, but had retinal pigment epithelial changes and arteriolar attenuation after 2 years old. In older children, peripheral mottling and sometimes peripheral punched-out chorioretinal lesions were seen. In those who underwent autofluorescence and optical coherence tomography (OCT), autofluorescence showed increased central macular signal and OCT showed loss of outer retinal structures. Clinical examples are provided in figures 13.

Table 1

Clinical summary

Figure 1

Subject 1: Retinal images are of the right eye; the left eye is not shown but was similar. (A) Fundus photograph of the right eye shows retinal pigment epithelial mottling and arteriolar attenuation. (B) Autofluorescence reveals increased signal in the central macula. (C) Optical coherence tomography reveals loss of outer retinal layers with relative preservation of inner retinal layers. (D) Cone-shaped phalangeal epiphyses can be appreciated on plain X-ray of the hands.

Figure 2

Subject 4: (A) At 1 year old, photophilia is evident. (B) At 2 years of age, eye rubbing (the oculo-digital sign) became common.

Figure 3

(Subject 10): Retinal images are of the left eye; the right eye is not shown but was similar. (A) Fundus photograph of the left eye shows retinal pigment epithelial mottling and arteriolar attenuation. (B) Mottling and outer retinal atrophy is more evident in the periphery, including occasional ‘punched-out’ lesions. (C) Autofluorescence shows a ring of increased signal in the central macula encircling the foveal area. There is also increased signal elsewhere in the posterior pole. (D and E) Optical coherence tomography reveals loss of outer retinal layers with relative preservation of inner retinal layers.


This cohort of 12 individuals (11 families) with confirmed IFT140-related retinopathy and five clinically affected relatives represents the largest such series to date. Retinopathy was congenital and severe, with no individual who underwent electrophysiology having a recordable ERG. The fundus appeared grossly normal before 1 year old but appeared dystrophic after 2 years of age. In early childhood, hyperopia, light staring and a happy demeanour were recurrent. Developmental delay was common and some children had frank skeletal or kidney disease; however, there were individuals for whom the ophthalmic phenotype seemed clinically isolated. All families except one harboured the same homozygous missense IFT140 mutation, suggesting it is a founder effect or mutational hotspot in the region.

Almost all of the 13 other reported families with biallelic IFT140 mutations were obviously syndromic and ophthalmic phenotypic details were limited. Perrault and colleagues5 described seven families with compound heterozygous or homozygous missense, splice or nonsense mutations. All had phalangeal cone-shaped epiphyses, and many had renal disease, developmental delay and/or short stature. All had a documented diagnosis of retinal dystrophy except two children from two families for whom the ophthalmic phenotype was not assessed. There were two Saudi Arabian families in that series, and both harboured the same homozygous recessive missense mutation we report. Interestingly, those were the only two families in that series without overt childhood renal disease, consistent with the fact that almost all of the children in our series did not have evident renal disease. Schmidts and colleagues6 reported six European patients from six families with compound heterozygous missense and/or nonsense IFT140 mutations; all had evidence for renal and skeletal disease and most appeared to have retinopathy, although the ophthalmic phenotype was not carefully assessed.

In our series, the retinal dystrophy associated with a homozygous IFT140 mutation was universally congenital and severe and associated with early childhood hyperopia. The early childhood phenotype of grossly normal fundus, high hyperopia and non-recordable ERG with or without neurodevelopmental delay overlaps with classic Leber congenital amaurosis.11 Infantile photophilia was a recurrent observation in our series and was also noted in one of the two Saudi families reported by Perrault and colleagues.5 Photophilia has been previously documented as recurrent for children with early childhood retinal dystrophies from biallelic mutations in RPE65, LRAT and PRPH2.12–14 Another recurrent observation we noted was a happy early childhood demeanour, an observation we have made before.3 Ours is the first series to document fundus appearance, autofluorescence and OCT for biallelic IFT140 mutations. In patients for whom these images were obtained, there was arteriolar narrowing and slight retinal pigment epithelium discolouration in the macula after 2 years old, peripheral mottling and sometimes punched out chorioretinal atrophy in older children, central macular increased signal by autofluorescence, and loss of outer retinal structures with relative preservation of inner structures by OCT.

A notable finding in our series is that individuals with IFT140-related retinopathy can be clinically non-syndromic, even as young adults. This was suggested by Perrault and colleagues in a 1-year-old Saudi girl5 and by us in a 10-month-old boy3 (subject 8 in the current report), but those children were still young at the time of assessment. In the current series, including affected relatives, 10/17 had developmental delay, 8/17 had evident skeletal disease and 1/17 had clinical renal disease. In one family three clinically affected siblings, currently 18, 20 and 25 years old, have excelled at school, with one of them winning a national academic prize. All six clinically affected children who had hand X-rays had phalangeal cone-shaped epiphyses. In the series by Perrault and colleagues,5 all 10 individuals who had X-rays also had cone-shaped epiphyses, whether or not there was an obvious skeletal phenotype. Although only one child in our series had clinical renal disease, it is important to note that variable expressivity for ciliopathies is a recognised phenomenon and that most children in this retrospective study did not have a careful work-up for subclinical renal disease.

There are limitations to our retrospective series. Data collection was limited by what was available in medical records and not all individuals had the same degree of clinical phenotypic assessment. Similarly, not all children had the same degree of ancillary investigations, for example, hand X-rays or renal function testing. However, we are able to define the ophthalmic phenotype associated with a homozygous IFT140 mutation and show that it can present without clinically evident extraocular manifestations, overlapping with Leber congenital amaurosis. IFT140 should be considered a candidate gene in children with severe congenital retinal dystrophy, especially if there is a skeletal or renal phenotype. Because IFT140 mutations can also cause apparent Leber congenital amaurosis, the gene should be included on Leber congenital amarosis gene panels. Given the nature of IFT140, it seems prudent that children identified with disease-causing mutations should have systemic follow-up whether or not they have apparent extraocular disease, particularly for renal function.


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  • Correction notice This article has been corrected since it was published Online First. Bold formatting has been removed from Table 1.

  • Contributors Substantial contributions to the conception or design of the work (AOK and HJB); or the acquisition, analysis, or interpretation of data for the work (INB, SME, HJB and AOK); drafting the work or revising it critically for important intellectual content (INB, SME, HJB and AOK); final approval of the version to be published (INB, SME, HJB and AOK); and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (INB, SME, HJB and AOK). The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Competing interests HJB is an employee of the company Bioscientia.

  • Patient consent Obtained.

  • Ethics approval KKESH IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Addendum While this article was in revision, the following relevant article was published: Xu M, Yang L, Wang F, et al. Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet Published Online First: 28 Jul 2015. doi:10.1007/s00439-015-1586-x

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