Novel homozygous mutation in the SPATA7 gene causes autosomal recessive retinal degeneration in a consanguineous German family

Retinitis pigmentosa (RP) is the term for a heterogeneous group of inherited eye disorders in which abnormalities of the photoreceptors or the retinal pigment epithelium lead to progressive vision loss. RP is the most common inherited retinal disease (IRD), estimated to affect 3 million people worldwide. Typical clinical features include night blindness and tunnel vision. In adulthood, many people with RP become legally blind. More than 60 genes have been associated with RP. SPATA7 (Gene ID: 55812; OMIM 609868) is known to cause autosomal recessive RP (with an estimated proportion of ~1%) and, in addition, leber congenital amaurosis (LCA), the earliest and most severe IRD. To date, 27 mutations in the SPATA7 gene have been reported (The Human Gene Mutation Database, HGMD. 2016). The c.1112T>C/p.I371T (RefSeq accession number NM_018418.4) variant has been detected in one LCA patient before. However, this patient carried the mutation heterozygously in addition to two likely causative compound heterozygous CRX mutations. Therefore, it remained unclear if it either represented an accidental carriership for a pathogenic allele (unrelated to the disease in that patient) or a non-pathogenic variant in a non-essential gene region. A morphological and functional description of this variant has yet been missing. We present the clinical and genetic findings of two siblings harboring the c.1112T>C/p.I371T homozygous mutation in the SPATA7 gene. The study was approved by the local ethics committee, and informed consent was obtained from all patients. A complete ophthalmological examination of the two affected siblings (female, 48 years; male, 52 years) of a German family and their non-affected mother was performed including psychophysical tests (best-corrected visual acuity, Lanthony Panel D-15 color vision test, visual field (VF), dark adaptation, and electrophysiology (fullfield and multifocal electroretinogram [ERG]). Additionally, fundus photography, autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT, Heidelberg Engineering GmbH, Heidelberg, Germany) were performed. Both patients showed typical findings of retinal degeneration; however, severity of disease varied (Table 1, Figure 1). The male sibling (52 years) was severely affected, while the female sibling (48 years) showed comparably mild symptoms. Their mother (85 years) showed normal age-related findings on all tests. The affected siblings were otherwise healthy and had no extraocular findings. Genomic DNA was analyzed using a capture panel of 286 syndromic and non-syndromic IRD genes. Details have already been published elsewhere. All putative mutations were validated and tested for co-segregation using conventional Sanger sequencing (3130XL Sequencer, Applied Biosystems, Weiterstadt, Germany). The potential pathogenicity of missense changes was assessed using SIFT [http://sift.bii. a-star.edu. sg/], PolyPhen-2 [http://genetics.bwh. harvard.edu/pph2/] and Mutation Taster [www.mutationtaster. org/]. Grantham and PhyloP scores were also determined. The ExAC browser [http://exac.broadinstitute. org/] was checked for minor allele frequencies. We identified the c.1112T>C/p.I371T missense variant in homozygous state in the SPATA7 gene with high-throughput panel sequencing in two siblings affected by retinal degeneration (Figure 2, Table 2). The parents were cousins of unknown degree. The mother was shown to be a heterozygous carrier. No DNA sample was available from the father. There were no other cases of retinal degeneration known in the family. The more severe findings of VF and ERG response in the male patient are in line with changes observed in previously described SPATA7 cases, in contrast to his sister. Since there was an age difference of 4 years between the siblings, difference in disease severity might be explained by disease progression over time, or/and by other factors such as modifying alleles. SPATA7 was first identified 2003 in testis and it was mapped to chromosome 14q31.3. In 2009, SPATA7 expression was shown in the retina, and the gene was firstly described as RPand LCA-causing. In 2014, SPATA7 was identified as a ciliary protein at the connecting cilium of photoreceptor cells. If SPATA7 is missing, proteins like rhodopsin accumulate. This triggers photoreceptor apoptosis leading to retinal degeneration. Since SPATA7 is highly conserved and since the phenotypes seen in humans and mice carrying SPATA7mutations are similar, the disease mechanism is likely to be the similar, too. The mutation spectrum of SPATA7 mainly comprises nonsense and splice site mutations as well as frameshift insertions and deletions. Apart from the c.1112T>C/p.I371T variant, only two other missense changes have been reported so far. Li et al. described a family in which the three affected