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BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Background Traboulsi syndrome is a very rare, syndromic form of ectopia lentis that is potentially sight-threatening at a young age. It is characterized by typical facial, skeletal and ocular signs. Materials and methods Two siblings, born to consanguineous parents, with a clinical phenotype consistent with Traboulsi syndrome, underwent extensive ophthalmic imaging and exome-based genetic testing. Both were treated with unilateral clear lens extraction via a limbal approach. Results Two siblings, one male and one female, presented with systemic and ocular features consistent with Traboulsi syndrome. Lens subluxation was present in all 4fouraffected eyes, and spontaneous subconjunctival bleb formation was detected in one eye. This eye also showed evidence of keratoconus-related corneal thinning. The clinical diagnosis of Traboulsi syndrome was confirmed molecularly. A homozygous, novel, pathogenic nonsense variant was identified in exon 25 of the ASPH gene: c.2181_2183dup, p.(Val727_Trp728insTer). Excellent visual outcomes following clear lens extraction and postoperative rigid gas-permeable contact lens fitting were obtained. Conclusions We expanded the genetic spectrum of Traboulsi syndrome with a novel frameshift variant in the ASPH gene. We showed that lensectomy followed by gas-permeable contact lenses is an efficient therapeutic approach to treat lens subluxation in Traboulsi syndrome. However, lifelong follow-up is crucial to avoid (late) postoperative complications.

Background: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype.Materials and methods: The medical records of the siblings were reviewed retrospectively.Results: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant.Conclusion: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.

The complete form of congenital stationary night blindness (cCSNB) represents a non-progressive retinal disorder characterized by night vision problems and often congenital nystagmus, reduced vision, high myopia, strabismus and normal fundus appearance. Clinically this form of CSNB can be diagnosed by full-field electroretinogram. The mode of inheritance can be X-linked and autosomal recessive with mutations in genes coding for proteins mainly present at the dendritic tips of ON-bipolar cells. Mutations in NYX, GRM6, GPR179, LRIT3 and TRPM1 lead to this condition. The latter gene defect represents the major form underlying cCSNBC. It codes for the melastatin-related transient receptor 1 expressed in the inner nuclear layer of the retina, with the protein localized in ON-bipolar cells. To date, various homozygous or compound heterozygous mutations in TRPM1 have been reported. Small chromosomal rearrangements are frequent cause of mental retardation. In rare cases deletions can overlap with a mutation on the remaining chromosome and lead to a recessive disorder. Here, we describe a patient with mild neurological deficiencies and cCSNB caused by a microdeletion on 15q32 overlapping with a TRPM1 variant.

North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. The disease is caused by non-coding single nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1.To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 gene promoters, and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays.Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two novel NCMD-associated non-coding SNVs that we identified. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, putting forward this region as a PRDM13 enhancer.Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis.Overall, this study gained insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.Graphical abstract

Purpose To illustrate with multimodal imaging a case of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) complicated by bilateral multifocal serous retinal detachments, subretinal exudation, and papilledema. Methods Case report. Fundus photography, spectral domain optical coherence tomography (SD-OCT), fluorescein angiography, and indocyanine green angiography were performed at presentation and the day after. We also present the SD-OCT follow-up at 8 days, 1 year, and 4 years. Results A 25-year-old 5-month-pregnant Guinean woman complained about decreased visual acuity in the right eye. Eye fundus and multimodal imaging were abnormal in both eyes. Spectral domain optical coherence tomography showed the presence of multifocal serous retinal detachments, subretinal deposits, and intraretinal cysts. Indocyanin green angiography revealed an irregular choroidal perfusion and localized choroidal ischemia. Spectral domain optical coherence tomography also provided assessment of retinal changes during the long-term follow-up, showing tissue damage in the outer retina. Conclusion Serous retinal detachments during pregnancy can be the leading sign of HELLP syndrome-a potentially life-threatening condition. Spectral domain optical coherence tomography is a noninvasive and useful tool for its diagnosis and follow-up. ICG is important to confirm the choroidal ischemia and choroidal vascular abnormalities, underlying conditions leading to main sign of HELLP syndrome in the eye.

We investigated a possible association between the acute onset of esotropia and tablet or smartphone use in children. We characterized the clinical aspects of esotropia associated with tablet or smartphone use. The medical records of 10 children aged between 5 and 15 years old with presumably tablet or smartphone associated esotropia were reviewed regarding orthoptic examination and cycloplegic refraction. Legal guardians of the children were asked to fill in a questionnaire regarding tablet and smartphone use of their child. This questionnaire was also conducted in a control group of age-matched children. The results of this questionnaire were compared to search for possible determinants of tablet or smartphone associated esotropia. All 10 patients presented with a comitant esotropia ranging from 8 to 45 prism diopters with no significant difference between near and far. The mean age of onset was 9.8 years. Cycloplegic refraction showed a mild hyperopia in eight patients, a mild myopia in one patient and emmetropia in the other patient. All patients had near full refractive correction at the onset of esotropia. Diplopia was reduced after visual hygiene recommendations, however in six patients, strabismus surgery was needed. The working distance was significantly shorter in the 10 cases compared to the controls. In children with acute acquired esotropia, we found a statistically significant association with a smaller working distance during tablet or smartphone use compared to age-matched controls. We hypothesize that intensive near viewing can be a precipitating factor in this type of esotropia.

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

ObjectiveExperimental evidence suggests that the clinical manifestations of Triple A syndrome result from oxidative stress. Several conditions caused by oxidative stress display retinal involvement. Our objective was to assess the retina and optic nerve involvement in children with Triple A syndrome.MethodsEleven patients with genetically proven Triple A syndrome followed-up in our centre were approached for study participation. The main outcome was the measurement of the thicknesses of the different retinal layers by Optical Coherence Tomography (OCT).Results9 patients with triple A syndrome had OCT measurements. 7 patients were children and 2 were adults; 4 were females and 5 were males. The 7 paediatric patients had at least two OCT measured at a mean interval of 7.9 months after the first one. The average Retinal Nerve Fibre Layer thickness was 74 ± 10 µm in patients compared to the paediatric reference range of 100 ± 2 µm (pConclusions and RelevanceThis is the first study to document retinal layer thicknesses in a series of patients with Triple A syndrome. Nearly all retinal thickness and peripapillary RNFL measurements were very significantly inferior to the reference range in Triple A patients, whatever their age. RNFL thinning was more marked at the temporal part of the optic nerve. OCT being non-invasive, it represents a promising tool to assess the severity of neurodegeneration in patients with Triple A syndrome.

The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, abnormal hypothalamus, and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations are reported to cause bilateral micro/anophthalmia without consistent associated features.Congenital Hypopituitarism can be associated with various eye or craniofacial anomalies but the co-occurrence of Congenital Hypopituitarism, anophthalmia, cleft palate and diabetes insipidus is very rare., SCOPUS: ar.j, info:eu-repo/semantics/published

PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders. ispartof: GENETICS IN MEDICINE vol:21 issue:8 pages:1761-1771 ispartof: location:United States status: published

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.

Primary congenital glaucoma is an important cause of visual impairment in children. It can develop both pre- and postnatally. Angle surgery is the first line treatment modality. If the disease remains untreated or if the diagnosis is delayed, it can lead to irreversible visual loss and blindness. The genetics of primary congenital glaucoma are complex and not yet entirely understood. At present multiple disease-causing genes have been identified. CYP1B1 is the most well known gene causing autosomal recessive congenital glaucoma. Other genes have been found to play a role through recessive, dominant or polygenic mechanisms. Here we provide an overview of the known genes and mechanisms described in patients with PCG. Furthermore, we provide a practical counseling and follow-up guideline for relatives of a proband.

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities. ispartof: Human Mutation vol:41 issue:5 pages:998-1011 ispartof: location:United States status: published

Background: Knobloch syndrome (OMIM 267750) is a rare autosomal recessive disorder due to genetic defects in the COL18A1 gene. The triad of high myopia, occipital defect, vitreoretinal degeneration has been described as pathognomonic for this condition. Patients with Knobloch syndrome have also extraocular problems as brain and kidney malformations. High genetic and phenotypic variation has been reported in the affected patients. Materials and Methods: Here we provide detailed clinical description of 3 individuals with Knobloch syndrome. Ocular examination and fundus imaging have been performed. Detailed information about systemic conditions has been provided. Results: Mutations in COL18A1 were identified in all three patients. Patient 1 had congenital hip dislocation and patient 2 had renal atrophy, cardiac insufficiency and difficult skin healing. Conclusions: With this report we add to the clinical and genetic knowledge of this rare condition., SCOPUS: ar.j, info:eu-repo/semantics/published

Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR. ispartof: European Journal of Medical Genetics vol:63 issue:5 ispartof: location:Netherlands status: published

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5′ untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.

Objective Age-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response. Methods and analysis A retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort. Results Association with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction. Conclusion Identifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.

Purpose To identify the molecular genetic cause in four families of various ethnic backgrounds with cornea plana. Methods Detailed ophthalmological examination and direct sequencing of the KERA coding region in five patients of Czech and Turkish origin and their available family members. Results Compound heterozygosity for a novel missense mutation c.209C>T; p.(Pro70Leu) and a novel splice site mutation c.887-1G>A in KERA were detected in two affected siblings of Czech origin. In silico analysis supported the pathogenicity of both variants. The second proband of Czech origin harboured c.835C>T; p.(Arg279*) in a homozygous state. Homozygous mutations c.740A>G; p.(Asn247Ser) and c.674C>T; p.(Ile225Thr) were identified in the Turkish probands, both born out of consanguineous marriages. Observed ocular phenotypes were typical of cornea plana with the exception of one Czech patient who also had marked thinning and protrusion in the superior part of the left cornea (mean keratometry 47.2 D). No corneal endothelial cell pathology was found by specular microscopy in seven eyes, in three eyes visualization of the posterior corneal surface was unsuccessful. Conclusion KERA mutation c.740A>G has been identified to date in three different populations, which makes it the most frequently occurring mutation in patients with cornea plana. Marked corneal thinning and ectasia are a very rare finding in this disorder and longitudinal follow-up needs to be performed to determine its potential progressive nature.

Introduction The clinical phenotype of the chromosome 2q31 deletion syndrome consists of limb anomalies ranging from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. Additional internal organ anomalies—for example, heart defects, ocular anomalies—may be present. Hemizygosity for HOXD13 and EVX2 genes was thought to cause the observed skeletal defects. Recently, based on the phenotype of patients with overlapping 2q31 interstitial deletions, a new SHFM5 locus was proposed, proximal to the HOXD cluster, between EVX2 and marker D2S294. DLX1 and DLX2 haploinsufficiency was suggested as the most plausible explanation for the observed SHFM-like limb anomalies in these cases. Methods and results Five unique, interstitial 2q31 deletion patients were selected to further characterise the 2q31 region and to establish a genotype/phenotype correlation map. The size of the deletions was delineated with a chromosome 2 specific tiling path bacterial artificial chromosome (BAC) array. The clinical and molecular data for this group of patients were compared to others in the literature. A common locus for the observed skeletal anomalies, including the HOXD genes and surrounding regulatory sequences, was delineated. These results correlate with recently published studies in animal models. In addition, a critical region for the facial gestalt of the 2q31.1 microdeletion syndrome was delineated. Conclusions These results reinforce the hypothesis that the variable skeletal phenotype in 2q31 deletion patients is a result of hemizygosity for the HOXD genes and that the 2q31.1 microdeletion syndrome is a well defined and clinically recognisable phenotype.

Branchio-oculo-facial syndrome (BOFS) is a rare disorder characterized by maldevelopment of the first and second branchial arches, skin defects, facial dysmorphism, auricular, ophthalmological and oral abnormalities. A high clinical variability has been reported. Recently, mutations in TFAP2A were found to underlie this condition. A small duplication on 5q13 was detected in 2 family members with mild BOFS features. Molecular cytogenetic delineation of the duplication demonstrated that only 7 genes are affected: LOC100289045, RGNEF, UTP15, ANKRA2, FUNDC2P1, BTF3 and FOXD1. The latter is expressed in the developing branchial arches and involved in cranio-facial development. Zebrafish embryos with combined inhibition of the expression of foxd1l and tfap2a show optic axis defects. We identified a novel locus associated with a mild BOFS-like phenotype. The functional in vivo experiments suggest an interaction between FOXD1 and TFAP2A.

Subtelomeric imbalances are identified in approximately 5% of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA). Because of this high incidence, screening for subtelomeric anomalies became part of the routine genetic evaluation of MCA/MR patients. In contrast to the general view that subtelomeric imbalances cause MCA/MR, we report here 15 subtelomeric copy-number changes in 12 families in which the imbalance is inherited from a phenotypically normal parent. We detected inherited deletions at subtelomeres 2q, 3p, 4p, 4q, 6q, 10q, 17p, 17q, Xp, and Yq and duplications at 1q, 4q, 10q, and 11q. Interestingly, in addition to small deletions (

BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5. METHODS: We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies. RESULTS: We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases. CONCLUSIONS: All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.

The acrofacial dysostoses (AFD) are a clinically and causally heterogeneous group of conditions characterized by mandibulofacial dysostosis and a variety of limb anomalies. Several abnormalities affecting different internal organs and the central nervous system (CNS) have been described. Depending on the type of limb defects, two major groups have been delineated: (1) with predominantly pre-axial anomalies, Nager type AFD, and (2) with predominantly post-axial involvement, Genee-Wiedemann form of AFD, also known as POADS, respectively. Other forms of "true AFD" have been described as Kelly, Reynolds, Arens (also Tel Aviv form), Rodriguez (or Madrid form), Richieri-Costa, and Patterson-Stevenson-Fontaine types. However, whether they are distinct entities or represent variants of the same condition remains unclear. Rodriguez AFD was described as a new lethal form of AFD in three affected sibs with severe mandibular hypoplasia, severe predominantly pre-axial limb deficiencies, absent fibulae and ribs, and internal organ anomalies, the most remarkable of which are arrhinencephaly and abnormal lung lobulation. We present a newborn girl with Rodriguez type of AFD, who died a few days after the birth due to respiratory failure. The phenotype and the cause of this condition are discussed.

A male patient, who had intra-uterine growth retardation, a low birth weight and hypotonia due to a chromosome 2q33.1 deletion, is described. At the age of 20 years, he displays short stature, microcephaly, a high forehead, microstomia, large teeth and is hypertonic. He is severely mentally retarded, has not developed speech, is hyperactive, anxious and at times aggressive. Full tiling array showed a de novo 14 Mb deletion at chromosome region 2q32.3q33.2, further delineating the 2q33.1 microdeletion syndrome.

We read with interest the article by Rivera-Brugues et al 1 in a recent issue of this journal describing 3 patients out of 1523 patients with unexplained mental retardation. Analysis by whole genome array-CGH (comparative genomic hybridisation) showed an intragenic heterozygous deletion in the VPS13B gene, and the subsequent sequencing of the VPS13B gene revealed by one-point mutation in the second allele in all three patients. In a previous study, we screened the VPS13B gene in 34 patients (28 families) with a suspicion of Cohen syndrome and identified 14 different mutations in 8 families (12 patients).2 The mutations were found in a compound heterozygous state in five families and in a homozygous state in one consanguineous family. In two other families (patients P1-F1, P2-F2 and P3-F2), only one heterozygous mutation was found (25% of families). Since the previous publication, 20 additional patients were screened, leading to the identification of compound heterozygosity in one patient and only one mutational event in four patients from three different families. All the patients with one or two mutational events in VPS13B were considered as having Cohen syndrome according to both Chandler's and Kolehmainen's criteria.3 4 Since the 244K array-CGH Agilent comprises 102 probes within the VPS13B gene (figure 1), we sought to identify a large intragenic event in two groups: group 1 included the five families in which one mutational event …

Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation.

We describe a female patient with der(2) t(2;10)(q37;q26). She presented with congenital malformations typical of a terminal 2q deletion, associated with immune deficiency leading to bronchiectasis.

BACKGROUND: Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10-15% of previously unnoticed de novo chromosomal imbalances. OBJECTIVE: To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype. RESULTS: Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified. CONCLUSIONS: Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims. ispartof: Journal of Medical Genetics vol:43 issue:8 pages:625-633 ispartof: location:England status: published

Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves.

The acrofacial dysostoses (AFD) are a clinically and causally heterogeneous group of conditions characterized by mandibulofacial dysostosis and a variety of limb anomalies. Several abnormalities affecting different internal organs and the central nervous system (CNS) have been described. Depending on the type of limb defects, two major groups have been delineated: (1) with predominantly pre-axial anomalies, Nager type AFD, and (2) with predominantly post-axial involvement, Genee-Wiedemann form of AFD, also known as POADS, respectively. Other forms of "true AFD" have been described as Kelly, Reynolds, Arens (also Tel Aviv form), Rodríguez (or Madrid form), Richieri-Costa, and Patterson-Stevenson-Fontaine types. However, whether they are distinct entities or represent variants of the same condition remains unclear. Rodríguez AFD was described as a new lethal form of AFD in three affected sibs with severe mandibular hypoplasia, severe predominantly pre-axial limb deficiencies, absent fibulae and ribs, and internal organ anomalies, the most remarkable of which are arrhinencephaly and abnormal lung lobulation. We present a newborn girl with Rodríguez type of AFD, who died a few days after the birth due to respiratory failure. The phenotype and the cause of this condition are discussed.

The application of array CGH or chromosomal microarrays is causing a revolutionary change in clinical genetics and especially cytogenetics, as it enables the genome wide identification of submicroscopic copy number variations (CNVs).1 Given the significant increase in diagnostic yield compared with conventional karyotyping in patients with intellectual disability (ID) and the technical ease of use, the technique is now recommended as a first tier diagnostic test for patients with ID and/or multiple congenital anomalies (MCA).2, 3 Arrays not only enable detection of disease-causing CNVs in patients with ID/MCA, but also in patients with isolated heart defects, neurological diseases and psychiatric disorders. Therefore, besides pediatricians and clinical geneticists, more and more other medical specialists request array analysis arrays.4, 5, 6, 7 In addition, there is a rapid implementation of array CGH in prenatal diagnosis.8, 9, 10, 11

Purpose The purpose of this study was to evaluate the clinical usefulness of the array comparative genomic hybridization technique for the genetic analysis of patients with congenital ocular malformations. Design Laboratory investigation. Methods This was a multicenter study. Samples were collected from 37 patients with negative results for the routine diagnostic work-up, including normal karyotype and mutation analysis of appropriate genes. Samples from both parents also were tested. High-resolution genome-wide Agilent 244K oligoarray (Agilent Technologies) was applied. Confirmation of the results was obtained with independent techniques. Results Causal deletions were identified in 5 (13%) patients, affecting OTX2, FOXC1 and VPS13B (COH1), the downstream regulatory region of PAX6, and a 1,5 Megabases de novo deletion on chromosome 16. Conclusions This high frequency of causal submicroscopic chromosomal aberrations in patients with congenital ocular malformation warrants implementation of array comparative genomic hybridization in the diagnostic work-up of these patients. Moreover, this screening technique broadens the phenotypic and mutational spectrum associated with genes known to cause congenital ocular malformation.

Recently, large-scale benign copy-number variations (CNVs)--encompassing over 12% of the genome and containing genes considered to be dosage tolerant for human development--were uncovered in the human population. Here we present a family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct. This phenotype is linked to a cytogenetically visible alteration at 4pter consisting of five copies of a copy-number-variable region, encompassing a low-copy repeat (LCR)-rich sequence. We demonstrate that the approximately 750 kb amplicon occurs in exact tandem copies. This is the first example of an amplified CNV associated with a Mendelian disorder, a discovery that implies that genome screens for genetic disorders should include the analysis of so-called benign CNVs and LCRs. ispartof: American Journal of Human Genetics vol:82 issue:1 pages:181-187 ispartof: location:United States status: published