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A Homozygous Nonsense Variant in IFT52 Is Associated with a Human Skeletal Ciliopathy

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A Homozygous Nonsense Variant in IFT52 Is Associated with a Human Skeletal Ciliopathy Clin Genet 2016 © 2016 John Wiley & Sons A/S. Printed in Singapore. All rights reserved Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12762 Short Report A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy a a Girisha K.M., Shukla A., Trujillano D., Bhavani G.S., Hebbar M., K. M. Girisha ,A.Shukla , Kadavigere R., Rolfs A. A homozygous nonsense variant in IFT52 is D. Trujillanob,G.S.Bhavania, associated with a human skeletal ciliopathy. M. Hebbara, R. Kadavigered Clin Genet 2016. © John Wiley & Sons A/S. Published by John Wiley & and A. Rolfsb,c Sons Ltd, 2016 aDepartment of Medical Genetics, Intraflagellar transport (IFT) is vital for the functioning of primary cilia. Kasturba Medical College, Manipal b Defects in several components of IFT complexes cause a spectrum of University, Manipal, India, Department of ciliopathies with variable involvement of skeleton, brain, eyes, ectoderm and Bioinformatics, Centogene AG, Rostock, Germany, cAlbrecht-Kossel-Institute for kidneys. We examined a child from a consanguineous family who had short Neuroregeneration, Medical University stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, Rostock, Rostock, Germany, and pigmentary retinopathy, small teeth and skeletal dysplasia. The clinical dDepartment of Radiodiagnosis and phenotype of the child shows significant overlap with cranioectodermal Imaging, Kasturba Medical College, dysplasia type I (Sensenbrenner syndrome). Whole-exome sequencing Manipal University, Manipal, India revealed a homozygous nonsense variant p.R142* in IFT52 encoding an Key words: chondrodysplasia – IFT-B core complex protein as the probable cause of her condition. This is ciliopathy – exome sequencing – the first report of a human disease associated with IFT52. intraflagellar transport – sensenbrenner syndrome – short rib thoracic dysplasia Conflictofinterest Corresponding author: Dr Katta M. None declared. Girisha, Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal 576104, India. Tel.: +91 820 2923149; fax: +91 820 2571934; e-mail: [email protected] Received 9 December 2015, revised and accepted for publication 12 February 2016 Human ciliopathies comprise a group of multisystemic Materials and methods genetic disorders caused by mutations in genes required Case report for ciliary assembly and maintenance (1). Defective intraflagellar transport (IFT) due to mutations in genes The proband was evaluated at 3 years of age. She was coding components of kinesin, dynein, IFT-A and IFT-B born at term by lower segment cesarean section to con- complexes are associated with a wide variety of human sanguineously married parents (Fig. S1). She weighed diseases with significant overlapping clinical features. 3.75 kg (normal) at birth. Bilateral postaxial polydactyly To date all IFT-A and five IFT-B components have in the hands was noted at birth and was surgically been reported to cause human diseases, most of which excised. Mild respiratory distress was evident in the are skeletal ciliopathies (Table S1, Supporting Infor- immediate newborn period and was managed symp- mation) (2). Mutations in genes encoding components tomatically. She had a significant delay of motoric func- of IFT-B core complex have been previously reported tions. She achieved neck holding at 18 months of age, with reno-ocular ciliopathies (3). Here we report the first sat at 2 years and walked without support at two and a human skeletal ciliopathy associated with a nonsense half years. Cognitive and language development are age variant in IFT52, encoding an IFT-B core complex appropriate. She speaks in complete sentences and is toi- protein. let trained. She had several episodes of wheezing and 1 Girisha et al. (a) (c) (e) (h) (f) (d) (b) (g) Fig. 1. Proband at 3 years of age has short limbs, narrow thorax, dolicocephaly, tall forehead, telecanthus, mid-face hypoplasia, depressed nasal bridge, thick and everted vermilion of upper and lower lips, small and widely spaced teeth and low set ears (a–d). She also has short hands with brachydactyly (e) and stump of surgically excised postaxial polydactyly on the right hand (arrow; f). Feet show sandal gap and brachydactyly (g). Chromatogram of proband shows homozygous nonsense mutation (c.424C > TinIFT52 NM_016004.3) and heterozygous status in parents for the same (h: proband – upper panel, mother – middle panel, father – lower panel). required bronchodilators. She has progressive deteriora- changes. The visual evoked potential and brainstem tion of peripheral vision and now has only central vision. evoked response audiometry study were normal. Her occipito-frontal circumference was 49.5 cm (nor- Vineland Social Maturity Scale revealed borderline mal), height 88 cm (normal) and weight 15 kg [+2 deficits in social and adaptive functioning. Her kary- standard deviation (SD), 85th centile] as per Cen- otype was normal. The parents consented for the study ter for Disease Control and Prevention growth charts and publication of photographs. The study has the (4). She had dolichocephaly, tall forehead, telecanthus, approval of institutional ethics committee. The pheno- mid-face hypoplasia, broad and depressed nasal bridge, typic information can be accessed at PhenomeCentral full cheeks, thick and everted vermilion of the upper and (https://www.phenomecentral.org/P0002186). lower lips and low set ears. Her teeth were small, widely spaced and carious. The thorax was short and narrow Chromosomal microarray with a protuberant abdomen. She had short limbs with marked brachydactyly and laxity in both hands and feet. Chromosomal microarray was performed using both The stumps of surgically excised postaxial polydactyly in copy number changes and single nucleotide poly- hands and sandal gap in feet were noted (Fig. 1). A soft morphism probes on a whole genome array (Illumina liver was palpable for 3 cm below the right costal mar- HumanCytoSNP-12, Illumina Inc., San Diego, CA) gin. Her gait was normal. She had nystagmus. Scalp hair from the peripheral blood DNA. All data were analyzed was normal. All other results of the systemic examination and reported using GenomeStudio and KaryoStudio were unremarkable. softwares (NCBI human genome build 37.1, hg19) Radiological survey at 3 years revealed short and follows International System for Cytogenetic metacarpals, short metatarsals, short phalanges, cone- Nomenclature (ISCN) guidelines. shaped epiphysis of phalanges, hypoplastic distal pha- langes and striking angel-shaped middle phalanges. A complete hemogram, liver function, renal parameters, Exome sequencing urinalysis were unremarkable. Ultrasound imaging Genomic DNA was extracted from the whole blood of the abdomen revealed normal liver and kidneys. using the standard phenol-chloroform method. Genomic Echocardiography revealed trivial tricuspid regurgita- capture was carried out with Illumina’s Nextera Rapid tion and mild pulmonary arterial hypertension without Capture Exome Kit. Massively parallel sequencing any structural malformations. Magnetic resonance was done using the NextSeq500 Sequencer (Illumina, imaging of the brain at 6 months of age showed a Inc., San Diego, CA, USA.) in combination with the hypoplastic corpus callosum (Fig. 2). Ophthalmology NextSeq™ 500 High Output Kit (2 × 150 bp). Raw evaluation revealed hypermetropia and salt and pepper sequencing reads were converted to standard fastq for- appearance of the fundus suggesting retinal degenerative mat using bcl2fastq software 2.17.1.14 (Illumina, Inc.), 2 A homozygous nonsense variant in IFT52 (a) (b) (c) (d) (h) (i) (e) (f) (g) (j) (k) (l) Fig. 2. Skeletal survey at age 3 years reveals an unremarkable skull (a, b), short and stubby metacarpals and phalanges, cone-shaped epiphysis of phalanges, hypoplastic distal phalanges and angel-shaped middle phalanges (c, d). Pelvis, hip joints, knee joints and lumbar vertebrae are unremarkable (f–i) and short metatarsals and phalanges in feet (j). Magnetic resonance imaging of the brain at 6 months of age shows hypoplastic corpus callosum (arrows; k, l). and fed to an in-house developed pipeline for the analysis cranioectodermal dysplasia type I (Sensenbrenner syn- of whole-exome sequencing (WES) data, based on the drome; MIM 218330), short rib polydactyly syndrome 1000 Genomes Project (1000G) data analysis pipeline type 3 (MIM 613091) and asphyxiating thoracic dyspla- and GATK best practice recommendations, which sia (MIM 263510) (5). Hence we expected a mutation includes widely used open source software projects. The in a gene encoding a protein in ciliary–centrosome short-reads are aligned to the GRCh37 (hg19) build of complex. Chromosomal microarray revealed no copy the human reference genome using bwa software with the number changes. A total of 16 regions of homozygosity mem algorithm. The alignments were converted to binary representing 3.1% of the genome were observed to bam file format, sorted on the fly and de-duplicated. include IFT52 on chromosome 20 (Table S4). On WES The primary alignment files for each sample are further of the trio, a homozygous nonsense pathogenic variant refined and augmented by additional information follow- p.R142* (c.424C > T, NM_016004.3) was identified ing GATK best practices recommendations. Afterwards in the proband in exon 6 of IFT52. No other sequence variant calling was performed on the secondary align- variants of pathogenic significance were detected in ment files using three different variant callers
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