New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform

Abstract

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

Expression of NMNAT1 in the photoreceptors is sufficient to prevent NMNAT1-associated retinal degeneration

“… 1 Although this gene is expressed ubiquitously, mutations in NMNAT1 primarily lead to retina-specific disease, with few reports of systemic disease. 1 , 2 , 3 , 4 , 5 In a small number of patients, structural variants in NMNAT1 have been reported to lead to systemic effects that manifest with a phenotype known as known as SHILCA, which is characterized by spondylo-epiphyseal dysplasia, sensorineural hearing loss, and intellectual disability, in addition to the Leber congenital amaurosis (LCA) phenotype. 2 , 6 Interestingly, patients with mutations in NMNAT1 have atrophy of the macula, 1 the region of the retina with a high density of cone photoreceptors, which are responsible for high-acuity central vision.…”

“… 1 , 2 , 3 , 4 , 5 In a small number of patients, structural variants in NMNAT1 have been reported to lead to systemic effects that manifest with a phenotype known as known as SHILCA, which is characterized by spondylo-epiphyseal dysplasia, sensorineural hearing loss, and intellectual disability, in addition to the Leber congenital amaurosis (LCA) phenotype. 2 , 6 Interestingly, patients with mutations in NMNAT1 have atrophy of the macula, 1 the region of the retina with a high density of cone photoreceptors, which are responsible for high-acuity central vision. There are currently no therapies approved by the Food and Drug Administration for NMNAT1 -associated disease, and the mechanisms underlying the retina-specific nature of this disease remain poorly understood.…”

Expression of NMNAT1 in the Photoreceptors is Sufficient to PreventNMNAT1-Associated Disease

“…Although this gene is expressed ubiquitously, mutations in NMNAT1 primarily lead to retina-specific disease, with few reports of systemic disease (1)(2)(3)(4)(5). In a small number of patients, structural variant (SVs) in NMNAT1 have been reported to lead to systemic effects manifest with a phenotype known as known as SHILCA, which is characterized by spondylo-epiphyseal dysplasia, sensorineural hearing loss, and intellectual disability, in addition to the LCA phenotype (2,6). Interestingly, patients with mutations in NMNAT1 have atrophy of the macula (1), the region of the retina with a high density of cone photoreceptors, which are responsible for high acuity central vision.…”

“…Mutations in the NMNAT1 gene lead to severe early onset inherited retinal degeneration (1). Although this gene is expressed ubiquitously, mutations in NMNAT1 primarily lead to retina-specific disease, with few reports of systemic disease (1)(2)(3)(4)(5). In a small number of patients, structural variant (SVs) in NMNAT1 have been reported to lead to systemic effects manifest with a phenotype known as known as SHILCA, which is characterized by spondylo-epiphyseal dysplasia, sensorineural hearing loss, and intellectual disability, in addition to the LCA phenotype (2,6).…”

Inherited Retinal Diseases

“…A large number of clinical trials targeting various IRD-related genes and mutations are currently ongoing. Comprehensive studies on the clinical spectrum and natural history associated with various IRD-causative genes and mutations are greatly important not only to define prognosis, but also to identify clinical trial endpoints [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”