In the previously reported families with autosomal dominant nonprogressive cerebellar ataxia (NPCA) [4, 7], mild to moderate early-onset NPCA, delayed motor milestones, and cerebellar vermal hypoplasia on imaging are consistent features. Although cognitive impairment is regarded as a characteristic feature of NPCA , only half of those families have cognitive impairment. In this Chinese family, the vertical mode of inheritance is consistent with autosomal dominant inheritance. Four patients of this family have a homogeneous phenotype and were characterized by CNPCA, motor developmental delays, postural and action tremor of the hand, dysarthria, and mild cognitive deficits. This phenotype is very similar to that observed in SCA29 . The family showed co-segregation of the mutation with the phenotype and its absence in normal unaffected individuals.
ITPR1 is known as causative gene of SCA including SCA15 and SCA29 . SCA15 is a rare, autosomal dominant, adult-onset, relatively slowly progressive ataxia with normal cognition . Cerebellar atrophy, particularly of the vermis, is the typical neuroradiological feature . SCA15 was first reported in 2001 , the locus mapping to chromosomal region 3p24.2-3pter [12, 13]. In 2007, partial deletions of the ITPR1 gene on the distal short arm of chromosome 3 was identified to cause SCA15 development [14, 15]. In 2001, Miyoshi et al.  reported a four-generation Japanese family with autosomal dominant spinocerebellar ataxia. Head MRI demonstrated cerebellar atrophy without brainstem involvement. Mutation analysis by PCR excluded mutations in previously identified genes causing SCA. Then, the disorder was designated as SCA16. Miura et al.  provided follow-up on this family and found that the contactin 4 gene locus at 3p26 is a candidate gene of SCA16. In 2008, Iwaki et al.  identified a heterozygous deletion of exons 1–48 of ITPR1 in SCA16 which indicated that SCA15 and SCA16 are the same disorder, due to haploinsufficiency of ITPR1.
In 2004, Dudding et al.  reported a four-generation Australian kindred of Caucasian ancestry with SCA29. All affected individuals had congenital onset of ataxia or delayed walking and wide-based gait as a young child with cognitive impairment of varying degrees. By genome-wide screen of a member of the family detected linkage to chromosome 3p with a maximum two-point lod score of 4.26 at D3S3630. The disease locus lies distal to D3S1304 in the pter region of chromosome 3. Approximately 8 cM of the candidate region overlaps with the locus defined for SCA15. However, their phenotypes are different. SCA29 is distinguished from SCA15 by onset in infancy of delayed motor development followed by NPCA and mild cognitive impairment. Additional variable features include nystagmus, dysarthria, and tremor . In 2012, Huang et al.  reported missense mutations in ITPR1 gene on chromosome 3p26-p25, which cause SCA29.
An ITPR1 point mutation was discovered in one family with SCA15  and two families with SCA29 . The expression level of ITPR1 mRNA and protein in SCA15 patients are lower than those in control subjects [14, 18, 19]. The missense mutation associated with SCA15 reduces the level of IP3R1 protein expression , resulting in reduced IP3R-mediated Ca2+ influx in the central nervous system and particularly in cerebellar Purkinje cells , which leads to persistent long-standing dysfunction of Purkinje cells and eventually degeneration of selective neuronal populations. Meanwhile, the molecular mechanisms responsible for SCA29 are poorly understood. We demonstrate in this study that a novel ITPR1 heterozygous mutations c. 1207-2A>T exists in this SCA29 family, splicing site that leads to rearrangements in ITPR1. Further analysis is required to understand functional effects of this mutation in SCA29.
In clinical practice, cerebellar ataxia, mental retardation, dysequilibrium syndrome and pontocerebellar hypoplasia present the similar phenotype with early-onset. However, both of them are passed on from generation to generation in line with autosomal recessive inheritance pattern.
Whole-exome sequencing is a diagnostic test for patients with nonspecific or unusual disease presentations of possible genetic cause . Now, WES is widely used to identify causative genetic mutations of diseases . For more definitive diagnosis, WES has been increasing applied to patients with cerebellar ataxia or cerebellar atrophy [23,24,25]. WES on an Illumina HiSeq 2500 platform also helped us to reveal a new mutation in causative genes for SCA29. Also, the findings of novel potential pathogenic variations provided inherited clues for further functional research. This study suggests that performing WES on affected individuals is an effective and cost-efficient method for mapping genes of rare Mendelian disorders.
ACMG guidelines  are strictly followed when variants were interpreted. This discovered variant, c.1207-2A>T of ITPR1 gene is a splice site mutation 2-bp upstream of exon 14, which would result in complete skipping of the exon 14 and loss of ITPR1 function. Several cases of ITPR1 loss of function mutations have been reported to be pathogenic [2, 26, 27], so c.1207-2A>T of ITPR1 gene meets condition of the ACMG guidelines as very strong pathogenic evidence (PVS1). In addition, this mutation is absent in 1000 Genomes (www.1000genomes.org), ESP6500 (evs.gs.washington.edu/EVS/), and ExAc (exac.broadinstitute.org/) databases. Therefore, the moderate pathogenic evidence (PM2) is also satisfied. The clinical features of disease caused by mutation of ITPR1 gene are highly consistent with this case. The c.1207-2A>T mutation is segregated within the family of the proband. This also supports pathogenic evidences (PP1 and PP4). Based on these facts, c.1207-2A>T of ITPR1 meets conditions of four pathogenic evidence (PVS1, PM2, PP1, and PP4), which should be categorized to be pathogenic according to the ACMG guideline of sequence varaints .
In conclusion, we identified a novel SCA29 causative splicing mutation of ITPR1 in a Chinese family. We suggest ITPR1 gene analysis shall be a priority for diagnosis of patients with early-onset CNPCA. WES is an efficient tool to analyze potential mutations.