NMNAT1 variants cause cone and cone-rod dystrophy

Nash, Benjamin; Symes, Richard; Goel, Himanshu; Dinger, Marcel E.; Bennetts, Bruce; Grigg, John; Jamieson, Robyn V

doi:10.1038/s41431-017-0029-7

Cited by 23 publications

(23 citation statements)

References 20 publications

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“…Several reports have described patients with COD/CORD showing a coloboma-like macular atrophy caused by pathogenic variants in several genes, such as NMNAT1, 51,52 ADAM9, 53 GUCA1A, 54 and GUCY2D. 55 In the present study, an intrachoroidal cavitation resembling coloboma-like macular atrophy was presented in three subjects bilaterally or unilaterally.…”

Section: Discussionsupporting

confidence: 58%

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Liu

Fujinami

Kuniyoshi

et al. 2020

Trans. Vis. Sci. Tech.

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To determine the clinical and genetic characteristics of patients with GUCY2Dassociated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal

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Section: Discussionsupporting

confidence: 58%

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Liu

Fujinami

Kuniyoshi

et al. 2020

Trans. Vis. Sci. Tech.

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“…The library preparation, genomic alignment, variant calling, and annotation were performed as previously described [5][6][7][8] with variant filtering undertaken for specific anterior segment, cataract, and microphthalmia/anophthalmia disease genes, as in our previous studies and review of ASD genes 4,5,8 (Supplementary Table 2). Average coverage of the key ASD genes was 93% and 92% above 20× in ES and GS platforms respectively.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Yousoof

Grigg

et al. 2020

Genetics in Medicine

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Purpose: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

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“…In line with the essential role of NAD + /NADH for basic cell metabolism, Nmnat1 knockout mice display embryonic lethality. In addition, no occurrence of biallelic null variants was ever observed in patients carrying homozygous or compound heterozygous NMNAT1 mutations among the 48 identified to date (10)(11)(12)(13)(14), suggesting that retinal degeneration results from reduced (although not completely absent) function of the NMNAT1 enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…NMNAT1 has been associated with LCA for the first time in 2012 (4,(7)(8)(9) and, since then, pathogenic variants in this gene have been identified in several individuals (10)(11)(12)(13)(14)(15), accounting for more than 5% of all forms of inherited retinal degenerations (3). NMNAT enzymes (NMNAT1, NMNAT2 and NMNAT3) play a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD) (16), catalyzing the condensation of nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN) to form NAD + or nicotinic acid dinucleotide (NaAD).…”

Section: Introductionmentioning

confidence: 99%

An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs

Bedoni

Quinodoz

Pinelli

et al. 2020

Human Molecular Genetics

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Abstract We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients’ fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.

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NMNAT1 variants cause cone and cone-rod dystrophy

Cited by 23 publications

References 20 publications

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs

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