Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family

Contains fulltext : 108199.pdf (publisher's version ) (Open Access)PURPOSE: The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP). METHODS: Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis. RESULTS: A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples. CONCLUSIONS: Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP

Mowat-Wilson syndrome: the first clinical and molecular report of an indonesian patient

Contains fulltext : 108738.pdf (publisher's version ) (Open Access)Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis

Duplication of 1q31.3q41 in two affected siblings due to paternal insertional translocation

Item does not contain fulltextWe report two sisters with developmental delay and dysmorphic features, as well as a history of seizures. Both sisters have short stature, microcephaly and shared facial dysmorphisms. We detected an 18.1 Mb interstitial gain in 1q31.3q41 and a 140 kb interstitial loss in 7p11.2 in both siblings by using array analysis in the older sister and copy number variation analysis in whole exome sequencing data in the younger sister. We further examined parental chromosomes and found an insertional translocation in the unaffected father, having a 46,XY,ins(7;1)(p11.2;q31.3q41) karyotype. A 1.8 Mb loss at the rearranged 1q segment was subsequently detected on additional array analysis in the father, as well as the 140 kb loss in 7p11.2. We describe the clinical consequences of the 18.1 Mb duplication of the long arm of chromosome 1 due to an unbalanced paternal insertional translocation and compare these with the clinical phenotypes of patients with an overlapping 1q duplication

Feasibility of preconception screening for thalassaemia in Indonesia: exploring the opinion of Javanese mothers

BACKGROUND: Thalassaemia has become a major public health issue in Indonesia. It has been estimated that up to 10% of the population carries a gene associated with beta-thalassaemia. Currently, there is no formal recommendation for thalassaemia screening. This study aimed to explore awareness of thalassaemia, and to explore attitudes regarding carrier testing among Javanese mothers. METHODS: A quantitative questionnaire, designed using constructs of the Theory of Planned Behaviour, was applied cross-sectionally. RESULTS: Out of 191 mothers who were invited, 180 agreed to participate (RR = 94%), of whom 74 had a child affected with thalassaemia. Both attitudes towards receiving information about thalassaemia, and attitudes towards carrier testing were very positive. Awareness of thalassaemia was poor. Mothers, both those with and without an affected child, had barely heard of thalassaemia, nor of carrier testing. However, all mothers, including those with an affected child expressed high levels of interest in carrier testing. Respondents did not perceive that they had any control over carrier testing, and feared stigmatization and being discriminated against if their carrier status was identified. Attitudes towards carrier testing explained 23% of future reproductive intentions, in addition to perceived stigmatization, education level and 'mother's age' (R (2)=0.44; p=0.001). CONCLUSION: Responding mothers expressed high levels of interest in receiving information on both thalassaemia and carrier testing. The less educated and the more deprived they were, the keener they were to receive this information. Overall, awareness of thalassaemia was low. Even mothers with affected children seemed unaware of the inheritance pattern and the recurrent risk of having an affected child in a subsequent pregnancy, showing the need for genetic counselling in Indonesia. It is therefore recommended not only to raise awareness about thalassaemia, but to improve the education of healthcare professionals as well. (aut. ref.

Surveillance and prevalence of fragile X syndrome in Indonesia

Item does not contain fulltextFragile X syndrome (FXS) is the most prevalent inherited cause of intellectual disability (ID) and autism spectrum disorder (ASD). Many studies have been conducted over the years, however, in Indonesia there is relatively less knowledge on the prevalence of FXS. We reviewed all studies involving FXS screening and cascade testing of the high-risk population in Indonesia for two decades, to elucidate the prevalence, as well as explore the presence of genetic clusters of FXS in Indonesia. The prevalence of FXS in the ID population of Indonesia ranged between 0.9-1.9%, while in the ASD population, the percentage was higher (6.15%). A screening and cascade testing conducted in a small village on Java Island showed a high prevalence of 45% in the ID population, suggesting a genetic cluster. The common ancestry of all affected individuals was suggestive of a founder effect in the region. Routine screening and subsequent cascade testing are essential, especially in cases of ID and ASD of unknown etiology in Indonesia

Mowat-Wilson syndrome: the first clinical and molecular report of an indonesian patient

Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis

Pathogenic variant in NFIX gene affecting three sisters due to paternal mosaicism

Contains fulltext : 229188.pdf (Publisher’s version ) (Closed access)We present a family with three girls presenting similar dysmorphic features, including overgrowth, intellectual disability, macrocephaly, prominent forehead, midface retrusion, strabismus, and scoliosis. Both parents were unaffected, suggesting the presence of an autosomal recessive syndrome. Following exome sequencing, a heterozygous nonsense variant was identified in the NFIX gene in all three siblings. The father appeared to have a low-grade (7%) mosaicism for this variant in his blood. Previously, de novo pathogenic variants in NFIX have been identified in Marshall-Smith syndrome and Malan syndrome, which share distinctive phenotypic features shared with the patients of the present family. This case emphasizes the importance of further molecular analysis especially in familial cases, to exclude the possibility of parental mosaicism

Molecular genetic analysis of retinitis pigmentosa in Indonesia using genome-wide homozygosity mapping

Contains fulltext : 98108.pdf (publisher's version ) (Open Access)PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous retinal disorder. Despite tremendous knowledge about the genes involved in RP, little is known about the genetic causes of RP in Indonesia. Here, we aim to identify the molecular genetic causes underlying RP in a small cohort of Indonesian patients, using genome-wide homozygosity mapping. METHODS: DNA samples from affected and healthy individuals from 14 Indonesian families segregating autosomal recessive, X-linked, or isolated RP were collected. Homozygosity mapping was conducted using Illumina 6k or Affymetrix 5.0 single nucleotide polymorphism (SNP) arrays. Known autosomal recessive RP (arRP) genes residing in homozygous regions and X-linked RP genes were sequenced for mutations. RESULTS: In ten out of the 14 families, homozygous regions were identified that contained genes known to be involved in the pathogenesis of RP. Sequence analysis of these genes revealed seven novel homozygous mutations in ATP-binding cassette, sub-family A, member 4 (ABCA4), crumbs homolog 1 (CRB1), eyes shut homolog (Drosophila) (EYS), c-mer proto-oncogene tyrosine kinase (MERTK), nuclear receptor subfamily 2, group E, member 3 (NR2E3) and phosphodiesterase 6A, cGMP-specific, rod, alpha (PDE6A), all segregating in the respective families. No mutations were identified in the X-linked genes retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (X-linked recessive; RP2). CONCLUSIONS: Homozygosity mapping is a powerful tool to identify the genetic defects underlying RP in the Indonesian population. Compared to studies involving patients from other populations, the same genes appear to be implicated in the etiology of recessive RP in Indonesia, although all mutations that were discovered are novel and as such may be unique for this population

The first family with adult osteogenesis imperfecta caused by a novel homozygous mutation in CREB3L1

Background: Osteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting collagen biosynthesis. Mutations in CREB3L1 encoding the ER stress transducer OASIS are very rare and are only reported in pediatric patients. We report a large family with a novel CREB3L1 mutation, with severe adult clinical presentation. Methods: Clinical examination was performed on the family members. Next generation sequencing was performed for the causative genes for OI. The mutation was confirmed in other family members with Sanger sequencing. Results: A novel homozygous mutation in CREB3L1 was identified in the three affected patients. The parents and siblings who carry the mutation in heterozygous state were clinically unaffected. The three affected siblings, who were reported to have been born healthy, presented very severe progressive skeletal malformations and joint contractures but absence of common OI characteristics including blue sclerae, deafness, and dentinogenesis imperfecta. Resorption of a part of the humerus presumably associated with fracture nonunion and pseudarthrosis. Conclusion: We report a novel homozygous CREB3L1 mutation in a large Indonesian family; the homozygous affected members have survived to adulthood and they present a more severe phenotype than previously reported, expanding the clinical spectrum of OI for this gene

Monosomy 9pter and trisomy 9q34.11qter in two sisters due to a maternal pericentric inversion

Pericentric inversions of chromosome 9 leading to unbalanced live-born offspring are relatively rare and so far only four cases have been reported. Here we present two sisters with an unbalanced recombinant chromosome 9 which resulted from a large maternal pericentric inversion inv(9)(p24.3q34.1). Further molecular characterisation of the aberrant chromosome 9 by 250k SNP array analysis showed a terminal 460 kb loss of 9p24.3 and a terminal 8.9 Mb gain of 9q34.11. We compared the clinical features of these two patients with the previous reported four cases as well as with patients with similar sized 9pter deletions or 9qter duplications. Based upon this study, we suggest that the recombinant chromosome 9 phenotype is mainly the result of duplication of a 3.4 Mb region of chromosome 9q34.11q34.13