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BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.
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Doenças Raras , Humanos , Índia/epidemiologia , Doenças Raras/genética , Estudos Retrospectivos , Masculino , Feminino , Centros de Atenção Terciária , Criança , Adulto , Adolescente , Pré-Escolar , Adulto Jovem , LactenteRESUMO
PURPOSE: Utilization of multimodal imaging techniques to diagnose cases of mucolipidosis type IV (ML-IV) and report a new genetic variant. METHODS: This study is a case report. RESULTS: Case 1 involves a 4-year-old boy with corneal haziness and global developmental delay who showed an increased reflectivity of the corneal epithelium on anterior segment optical coherence tomography (AS-OCT). In addition, neurologic evaluation was suggestive of ML-IV. Further genetics evaluation confirmed ML-IV. Histology of the button revealed a thickened epithelial basement membrane. Case 2, the younger sibling, showed a milder corneal haze with similar changes on AS-OCT prompting us to further evaluate for ML-IV by genetics (positive MCOLN1 gene mutation). Both instances highlighted varied ML-IV presentations, but a persistent feature was hyperreflective epithelium. CONCLUSIONS: Our study emphasizes AS-OCT's role in screening ML-IV and advocates the role of genetic counseling of affected parents. We present 2 South-Asian siblings with ML-IV with a new genetic variant, emphasizing the utility of detailed ophthalmic and neurologic assessments using multimodal imaging.
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BACKGROUND: Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India. RESULTS: 903 smMIPs were designed to target exon and exon-intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood. CONCLUSION: We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.
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Variações do Número de Cópias de DNA , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Doenças por Armazenamento dos Lisossomos , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/diagnóstico , Índia , Variações do Número de Cópias de DNA/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único/genética , Feminino , Masculino , Sondas Moleculares/genéticaRESUMO
The genetic influences on human growth are being increasingly deciphered. Silver-Russell and Beckwith-Wiedemann syndromes (SRS; BWS) are two relatively common genetic syndromes with under- and overgrowth-related issues being the reason for referral. Aberration in genomic imprinting is the underlying genetic pathomechanism behind these syndromes. Herein, we described a series of children with these two growth disorders and give an orientation to the reader of the concept of imprinting as well as the genetic testing strategy and counseling to be offered in these syndromes.
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Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.
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Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes.
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Background: In the hypothalamic-pituitary-gonadotrophin (HPG) axis, estrogen plays a key role in the bone maturation regulation and growth plates closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in the North Indian population. Methods: Four SNPs of the ESR1 gene (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in 52 ISS patients and 68 controls. Linkage disequilibrium (LD) and haplotyping were done by SNPstat and SHESISplus softwares. Extent of LD was determined by calculating D' and r2 values in SNPs paired combinations. Results: A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility as compared to controls. The frequencies of the rs6557177 CC genotype (p=0.030; OR=0.13; 95% CI:0.01-1.10) and rs543650 genotype TT (p =0.043; OR=0.29; 95% CI: 0.09-0.92) were observed to be increased in ISS group as compared with the control group. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 shown strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Conclusion: Our study showed that CC genotype at rs6557177 and TT genotype of rs543650 of ESR1 constitutes risk factor for developing ISS in North Indian children. In the future, these findings may lead to a better understanding of the SNPs associated with ISS susceptibility.
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BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
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Alelos , Instabilidade Articular , Fatores de Transcrição , Humanos , Feminino , Adulto Jovem , Fatores de Transcrição/genética , Instabilidade Articular/genética , Instabilidade Articular/diagnóstico , Instabilidade Articular/congênito , Índia , Anormalidades da Pele/genética , Anormalidades da Pele/diagnóstico , Aracnodactilia/genética , Aracnodactilia/diagnóstico , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Linhagem , Mutação , Éxons/genética , Anormalidades Múltiplas/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologiaRESUMO
Background: Neurofibromatosis type 1 (NF1) is a unique, highly penetrant neuro-cutaneous disorder with a wide range of manifestations. Though the clinical diagnosis of NF1 is straight forward, there can be other disorders which mimic NF1, especially its cutaneous features. Here we describe the clinical and mutation spectrum of a series of individuals whose primary diagnosis was NF1 or NF1 related disorders. Methods: We have screened 29 unrelated individuals who fulfilled the clinical criteria of NF1. Whole exome sequencing (WES) was done in all individuals except one with suspected microdeletion syndrome with NF1 in whom Cytogenetic microarray (CMA) was done. Results: Out of 29 suspected patients, 25 had germline pathogenic/likely pathogenic variants involving NF1 gene. Five novel and 20 known variants in coding and non-coding regions were identified, among them 7 variants were deletions (28%), 7 nonsense (28%), 3 splice-site (12%), 4 missense (16%), 2 duplications (8%) and 2 (8%) were contiguous deletions. In those where NF1 variants were not detected, 3 had neurofibromatosis type 2 (NF2) and 1 rare autosomal recessive form of Elher Danlos syndrome. Conclusion: We hereby present the wide range of manifestations in different age groups and the mutation spectrum ranging from small scale variants to contiguous gene deletion syndromes involving NF1 gene. We highlight the usefulness of molecular testing and its importance in tumor surveillance and genetic counseling in this disorder.
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BACKGROUND: Treg cells play an important role in development of tolerance in maternal immune system against the semi-allogenic embryo. Human forkhead box protein 3 (FOXP3) gene, is the major transcription factor responsible for the regulation of Treg function during pregnancy. Single nucleotide polymorphisms (SNPs) of FOXP3 gene have been reported as a risk factor for Recurrent Pregnancy Loss (RPL), however, results from previous studies are inconsistent. METHODOLOGY: We have collected data from different studies to investigate the overall association of FOXP3 SNPs with risk of RPL. PubMed, Google Scholar, Elsevier, and Cochrane databases were searched to identify eligible studies. Odds Ratio (OR) and 95 % Confidence Interval (CI), calculated via fixed effect or random effect models, were used to evaluate strength of association. This meta-analysis included 11 studies (1383 RPL cases and 1413 controls) of 6 SNPs: rs3761548 A/C, rs2232365 A/G, rs2294021 T/C, 2280883 T/C, rs5902434del/ATT and rs141704699C/T, with ≥2 studies per SNPs and at least 1 significant result. RESULTS: We observed that FOXP3 polymorphism was predominantly present in Asian women with history of RPL. rs2232365 A/G, rs3761548 A/C, rs2294021 T/C, rs2280883 T/C and rs5902434del/ATT polymorphisms were significantly associated with risk of RPL in Indian population. Further, among the most commonly seen polymorphism, rs3761548 A/C was significantly associated with risk of RPL in women from Kazakhstan, China and Gaza, Palestine; rs2232365 A/G in populations of Kazakhstan, Egypt, Iran and Gaza, Palestine. Results of this study indicates that FOXP3 polymorphism is significantly associated with risk of RPL, especially in Asians.
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Aborto Habitual , Povo Asiático , Fatores de Transcrição Forkhead , População do Oriente Médio e Norte da África , Feminino , Humanos , Gravidez , Aborto Habitual/etnologia , Aborto Habitual/genética , Povo Asiático/etnologia , Povo Asiático/genética , Estudos de Casos e Controles , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único/genética , População do Oriente Médio e Norte da África/genéticaRESUMO
Objective: Short stature homeobox (SHOX) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.
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Nanismo , Osteocondrodisplasias , Criança , Feminino , Humanos , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteína de Homoeobox de Baixa Estatura/genética , Nanismo/epidemiologia , Nanismo/genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/genética , Índia/epidemiologia , Osteocondrodisplasias/genéticaRESUMO
OBJECTIVE: Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children. METHODS: Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed. RESULTS: Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy. SIGNIFICANCE: Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.
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Síndrome de Down , Espasmos Infantis , Masculino , Humanos , Criança , Lactente , Feminino , Estudos Transversais , Espasmos Infantis/genética , Convulsões/genética , Espasmo , N-AcetilglucosaminiltransferasesRESUMO
Background: Diphtheria, Tetanus, and whole-cell Pertussis (DTwP) vaccination-associated seizures form the commonest type of serious adverse event following immunization in India and are an important reason for vaccine hesitancy. Our study explored the genetic explanation of DTwP vaccination-associated seizures or subsequent epilepsies. Methods: Between March 2017 and March 2019, we screened 67 children with DTwP vaccination-associated seizures or subsequent epilepsies, and of those, we studied 54 without prior seizures or neurodevelopmental deficits. Our study design was cross-sectional with a 1-year follow-up having both retrospective and prospective cases. We performed clinical exome sequencing focused on 157 epilepsy-associated genes and multiplex ligation-dependent probe amplification of the SCN1A gene at enrolment. We applied the Vineland Social Maturity Scale for neurodevelopmental assessment at follow-up. Findings: Of 54 children enrolled and underwent genetic testing (median age 37.5 months, interquartile range 7.7-67.2; diagnosis at enrolment: epilepsy 29, febrile seizure 21, and febrile seizure-plus 4), we found 33 pathogenic variants of 12 genes. Of 33 variants, 13 (39%) were novel. Most pathogenic variants were found in SCN1A gene (n = 21/33; 64%), SCN8A in 2 children, and 10 children had one variant in CDKL5, DEPDC5, GNAO1, KCNA2, KCNT1, KCNQ2, NPRL3, PCDH19, RHOBTB2, and SLC2A1. Five or more seizures (odds ratio [OR] = 5.3, confidence interval [CI]: 1.6-18.4, p = 0.006), drug-resistant epilepsy (OR = 9.8, 95% CI: 2.6-30.7, p = 0.001) and neurodevelopmental impairment (social quotient < 70) (OR = 5.6, 95% CI: 1.65-17.6, p = 0.006) were significant predictors of genetic diagnosis. Interpretation: Our study provides proof-of-concept for genetic aetiology in children with DTwP vaccination-associated seizures or subsequent epilepsies and has important implications for vaccination policies in developing countries. Funding: International Pediatric Association Foundation, Inc. (IPAF): Ihsan Dogramaci research award 2016/2017; Indian Council of Medical Research (ICMR), New Delhi, India: No.3/1/3/JRF-2016/HRD/LS/71/10940.
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Background: Recurrent pregnancy loss (RPL) is one of the most common pregnancy-related complications, which can be stressful and emotionally draining for a couple. Genetic alterations, which are responsible for RPL, can be present in either of the three genomes: mother, father, or their fetuses. In addition, environmental factors interacting with these three genomes can affect germline cells. With this aim, the present study was conducted to understand the underlying etiology of RPL using Next-generation sequencing (NGS; couple exome and TRIO exomes) in combination with cytogenetic tests [karyotyping and chromosomal microarray (CMA)]. Material & Methods: In present study we recruited 61 couples with RPL (history of ≥ 2 abortions) and 31 products of conceptions (POCs). For all couples karyotyping was done at the time of recruitment, followed by collection of POC samples and parental blood samples. Before processing POC samples for CMA, they were checked for maternal cell contamination (MCC) by QF-PCR. In POC samples with no pathogenic variant, TRIO exome sequencing was done. Further, in case of unavailability of POC sample, couple exome sequencing was done for RPL couples. Results: In six individuals out of 61 couples (5%), abnormality in karyotypes was detected. Among 116 normal karyotypes, there were 11 heteromorphisms (9.5%), for which the couples had to be counselled and reassured. Out of the 31 POCs, 10 were excluded because of MCC (around 30%) and one had major aneuploidy. CMA in POCs identified pathogenic copy number variations (CNVs) in 25% of cases (5/20) and variant of unknown significance (VUS) in 20% of cases (4/20). Autosomal trisomy was the most frequent chromosomal abnormality diagnosed. NGS was performed to establish single-gene causes of RPL. Couple exome sequencing was performed in 20 couples, and 14 were found to be carriers for autosomal recessive conditions. A total of 50 potential disease-causing variants in 40 genes were identified in 33 of 40 individuals (82.5%). Putative causative variants were identified in 37.5% of the TRIO cases (3/8). Mutations in few important genes (SRP54, ERBB4, NEB, ALMS, ALAD, MTHFR, F5, and APOE), which are involved in vital pathways, early embryonic development, and fetal demise, were identified in the POCs. Conclusion: It enhances our understanding of prenatal phenotypes of many Mendelian disorders. These mutated genes may play an auxiliary role in the development of treatment strategies for RPL. There was no correlation of the number of abortions with etiological yield of any technique to detect the cause of RPL. This study shows the utilization of combination of techniques in improving our understanding of the cause of early embryonic lethality in humans.
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Purpose: Hereditary causes are an important etiological category of childhood blindness. This study reports the real-world experience of a developing ocular genetic service. Methods: The study was carried out from Jan 2020 to Dec 2021 jointly by the Pediatric Genetic Clinic and the Department of Ophthalmology of a tertiary care hospital in North-West India. Children presenting to the genetic clinic with congenital or late-onset ocular disorder(s) and any individual (irrespective of age) suffering from an ophthalmic disorder and referred by an ophthalmologist for genetic counseling for himself/herself and/or his/her family member(s) were included. Genetic testing (exome sequencing/panel-based sequencing/chromosomal microarray) was outsourced to third-party laboratories with the cost of the test being borne by the patient. Results: Exactly 8.6% of the registered patients in the genetic clinic had ocular disorders. Maximum number of patients belonged to the category of anterior segment dysgenesis, followed by microphthalmia anophthalmia coloboma spectrum, lens disorders, and inherited retinal disorders in decreasing numbers. The ratio of syndromic ocular to isolated ocular disorders seen was 1.8:1. Genetic testing was accepted by 55.5% of families. The genetic testing was clinically useful for ~35% of the tested cohort, with the opportunity for prenatal diagnosis being the most useful application of genetic testing. Conclusion: Syndromic ocular disorders are seen at a higher frequency compared to isolated ocular disorders in a genetic clinic. Opportunity for prenatal diagnosis is the most useful application of genetic testing in ocular disorders.
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Anormalidades do Olho , Face , Humanos , Feminino , Masculino , Criança , Gravidez , Serviços em Genética , Testes Genéticos , RetinaRESUMO
Rubinstein-Taybi syndrome, also known as broad thumb-hallux syndrome, is a rare autosomal dominant genetic disorder. This multiorgan syndrome is linked to a pathogenic mutation in the CREBBP or EBP300 genes.We present a patient with a hitherto unreported constellation of anterior segment abnormalities, including congenital glaucoma, congenital corneal keloid, cataract, and distinct facial and systemic features including a high-arched palate, low-set posteriorly rotated ears, Café-au-lait spots on the back, broad terminal phalanges of hands and feet, and bilateral cryptorchidism. The characteristic dysgenetic angle features and ultrasound biomicroscopic findings described in this case report show the occurrence of concomitant congenital keloid with glaucoma.Genetic testing revealed a heterozygous one-base pair duplication in exon 3 of the CREBBP gene (c.886dupC), a novel frameshift pathogenic mutation in the CREBBP gene that has not been previously reported in a clinical setting.
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Glaucoma , Hidroftalmia , Queloide , Síndrome de Rubinstein-Taybi , Masculino , Humanos , Lactente , Síndrome de Rubinstein-Taybi/complicações , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Mutação , Mutação da Fase de Leitura , Proteína de Ligação a CREB/genéticaRESUMO
This retrospective study was performed on 208 patients with Down syndrome (DS) from heterogeneous ethnic population and admitted under Genetics Metabolic Unit. The aim of the study was to look for phenotypic variability and associated complications in children and adolescents with DS. The average age of the evaluated DS patients was 34 months. Cardiac anomalies were found in 128 (62%) of the 208 cases. Among the cardiac disorders, atrial septal defects accounted for 30% of cases. Other complications observed were hypothyroidism and developmental delay in around 31% cases and neonatal cholestasis in 14% cases. Also, we report two cases with Moya-Moya disease and one case with atlanto-axial dislocation.