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. 2017 Jul 31;8(35):59446–59454. doi: 10.18632/oncotarget.19739

Family-based whole exome sequencing of atopic dermatitis complicated with cataracts

Wenxin Luo 1,*, Wangdong Xu 2,*, Lin Xia 3, Dan Xie 3, Lin Wang 4, Zaipei Guo 5, Yue Cheng 1, Yi Liu 2, Weimin Li 1
PMCID: PMC5601745  PMID: 28938649

Abstract

Background

Atopic dermatitis (AD) is a common skin disorder with elevated prevalence. Cataract induced by AD rarely occurs in adolescent and young adult patients, which is also called atopic cataract. Using whole exome sequencing, we aimed to explore genetic alterations among AD and atopic cataract.

Result

We recruited a 19 year-old Chinese male with AD accompanied with cataracts, his father with AD and his mother without AD or cataract. Through analysis of the exomic sequence of the 3 individuals from the same family, we identified that with respect to AD, there were 162 genes mutated in both this patient and his father but not in his mother. In addition, we found 10 genes mutated in this patient only without in his parents according to cataract.

Conclusion

This research suggests that coinheritance of mutations in these genes may correlate with AD, and the pathogenesis of AD complicated with cataracts was related to genetic factors.

Keywords: atopic dermatitis, cataracts, mutation

INTRODUCTION

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with a worldwide prevalence of 8.7-18.1% in children [1] and 1.5-10.2% in adults [2]. It is characterized by continual itchiness, flares and sleep disturbance, negatively regulating the occupational activities and social relationships of patients, the quality of life of patients and their families [3]. Studies have convinced of a combination of genetic and environmental factors in the pathogenesis of AD. Genetic evidence depicts a complex network comprising epidermal barrier dysfunctions and dysregulation of innate and adaptive immunity in this disease. It has been accepted that mutations in the human filaggrin (FLG) gene are the most significant and well-replicated genetic mutations related to AD. Some other mutations such as SPINK5, SPRR3, and CLDN1 may also correlate with epidermal barriers linked to AD. Genetic variants are able to contribute to the abnormal innate and adaptive responses, such as mutations in IL-1 family cytokines and receptors genes, vitamin D pathway genes, Th2 cytokines genes [4]. A cataract is a clouding of the lens that reduces light transmission to the retina, and it decreases the visual acuity of the bearer. It is one of the severe ocular complications of AD manifested in the eyes. The general classification of cataract includes nuclear, cortical and posterior subcapsular subtypes. Here, we focused on a Chinese male with AD complicated with cataracts via the recently developed whole exome sequencing approach, which has been used to determine the genetic basis of rare diseases.

RESULTS

Clinical description

The patient was a 19 year-old Chinese male who was admitted to our hospital with the chief complaint of relapsing generalized skin rash and blurred vision in August, 2015. His rash began from 10 years ago, accompanied with diffuse red papules all over the body, white desquamation, and skin itchiness. He was diagnosed with AD, and treatment without corticosteroids was not effective. There were persistent skin lesions, with obvious itchiness. His skin became dry and flaking, and some area became hard and thick. Seven months ago, his binocular vision became gradually declined. When admitted, red papules and scratches were displayed on the face, neck, trunk, and four extremities, especially on the face and neck (Figure 1). Both eyelids were hard and thick. The right vision was 0.4, and the left vision was 0.1. Keratic precipitates were negative, but both lens were turbid (Figure 2), of which the right one was more severe than the left. Hemogram analysis revealed eosinophile granulocyte 0.8×109/l (12.1% in WBC), and immunological studies showed that expression of IgE was strongly elevated (>3000.00IU/ml). Other investigations such as expression of complements, immune complex, subpopulation of T cells, anti-double stranded DNA antibody, anti-nuclear antibody were normal. Serum allergen test indicated that combination of willow/poplar/elm, crab, shrimp, combination of dermatophagoides pteronyssinus/dermatophagoides culinae were positive allergens. He has a history of eczema and house dust allergy. Interestingly, his father and grandma were diagnosed with AD, respectively (Figure 3).

Figure 1. Appearance of red papules and scratches in the young patient.

Figure 1

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Figure 2. Anterior subcapsular cataracts and posterior subcapsular cataracts in both lens.

Figure 2

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Figure 3. Family pedigree of the atopic dermatitis.

Figure 3

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Genetic analysis

Due to the rarity of cataract occurred in this young male with AD, we hypothesized that an underlying genetic alteration might be present in this patient. We discussed the genetic relationship between the patient and his parents by whole exome sequencing. In order to discover the candidate mutations of AD, we searched for the genes both mutated in this patient and his father but not in his mother. Results showed that 162 genes were both mutated in this patient and his father but not in his mother (Table 1, Supplementary Table 1).

Table 1. List of 162 genes both mutated in the patient and his father by whole exome sequencing.

Chromosome Position Gene SNP Chromosome Position Gene SNP
chr1 93646190 TMED5 rs185712821 C/T chr10 75563726 NDST2 NA C/T
chr1 45271238 PLK3 rs55654497 G/A chr11 5537592 UBQLNL rs142657773 G/C
chr1 162569107 UAP1 rs190156359 T/A chr11 74915493 SLCO2B1 rs192050675 C/A
chr1 214537946 PTPN14 rs200340171 G/A chr11 78369215 TENM4 rs185503085 C/T
chr1 109260438 FNDC7 NA T/C chr11 123988461 VWA5A rs202202178 A/T
chr1 158533225 OR6P1 NA C/T chr11 124266877 OR8B3 rs183842912 A/C
chr1 16907303 NBPF1 rs681623 C/T chr11 10585620 LYVE1 NA G/T
chr1 17083872 MST1L rs11545933 G/A chr11 118376389 KMT2A NA C/T
chr1 17263277 CROCC rs200228265 G/A chr11 130060375 ST14 NA C/T
chr1 181019227 MR1 NA G/A chr11 3726498 NUP98 NA G/A
chr1 232561368 SIPA1L2 NA C/A chr11 6661388 DCHS1 rs147698268 G/A
chr1 23637401 HNRNPR NA C/T chr11 71249529 KRTAP5-8 rs200162819 G/A
chr1 248813827 OR2T27 rs1782241 T/C chr12 6669359 NOP2 rs142370738 G/C
chr1 33237103 KIAA1522 NA C/T chr12 7475081 ACSM4 rs7485773 C/T
chr1 57411713 C8B NA G/C chr12 105464439 ALDH1L2 rs199841702 G/C
chr1 86355260 COL24A1 NA C/G chr12 109217071 SSH1 rs140582047 T/A
chr1 9780232 PIK3CD NA G/A chr12 110221524 TRPV4 rs55728855 C/T
chr2 90249249 IGKV1D-43 NA T/C chr12 112150408 ACAD10 rs145407775 C/T
chr2 113343610 CHCHD5 rs199612227 A/G chr12 124097777 DDX55 rs117200049 G/A
chr2 209108226 IDH1 rs186787509 T/C chr12 108956430 ISCU NA G/C
chr2 233735070 C2orf82 rs200597442 C/G chr12 11183661 TAS2R31 NA C/A
chr2 152484095 NEB NA C/G chr12 12966365 DDX47 NA G/A
chr2 179466289 TTN NA C/T chr12 48104624 ENDOU NA C/T
chr2 187627500 FAM171B NA A/G chr12 52885339 KRT6A rs199613662 C/T
chr2 233675986 GIGYF2 NA A/G chr12 6950473 GNB3 NA C/T
chr2 73315216 RAB11FIP5 NA A/T chr13 103419820 TEX30 rs200314758 T/C
chr2 97877478 ANKRD36 rs10194525 G/A chr13 96242562 DZIP1 NA T/G
chr3 7728055 GRM7 rs182447901 C/T chr14 45432003 FAM179B rs200775208 C/T
chr3 33644578 CLASP2 rs117166070 C/T chr14 68241828 ZFYVE26 rs193244014 G/C
chr3 49751251 RNF123 rs117758999 G/A chr14 105415264 AHNAK2 rs201041268 G/A
chr3 112648174 CD200R1 rs188572017 A/T chr14 32256995 NUBPL NA G/A
chr3 151107788 MED12L rs199780529 T/C chr14 70925106 ADAM21 NA T/C
chr3 124351317 KALRN NA G/A chr15 45456025 DUOX1 rs186783799 G/A
chr3 132319977 CCRL1 NA G/A chr15 89402346 ACAN rs188663484 T/C
chr3 40442466 ENTPD3 rs140869368 G/A chr16 21994499 UQCRC2 NA T/A
chr4 42119545 BEND4 rs187366202 G/T chr16 15761154 NDE1 rs147283674 C/T
chr4 47788868 CORIN rs186748019 C/A chr16 55530864 MMP2 rs28730814 G/A
chr4 52948557 SPATA18 rs184617860 C/T chr16 18849442 SMG1 NA G/A
chr4 186291928 LRP2BP NA C/T chr16 2287576 DNASE1L2 NA C/T
chr4 4190576 OTOP1 rs2215642 C/G chr16 28846489 ATXN2L NA T/C
chr5 38451559 EGFLAM rs140968262 A/G chr16 30100451 TBX6 rs202193096 G/A
chr5 94814011 TTC37 rs143227096 C/A chr16 456349 DECR2 NA C/T
chr5 137722246 KDM3B rs184734460 C/G chr16 46637519 SHCBP1 NA A/G
chr5 178507048 ZNF354C rs116562180 C/G chr16 67991689 SLC12A4 NA G/A
chr5 128442753 ISOC1 NA G/T chr16 71163611 HYDIN NA T/G
chr5 149357850 SLC26A2 NA G/T chr16 71961625 IST1 NA C/G
chr5 171341357 FBXW11 NA G/T chr16 84213027 TAF1C NA C/G
chr6 26056145 HIST1H1C rs79483116 G/A chr17 76166705 SYNGR2 NA G/A
chr6 27277365 POM121L2 rs61736085 G/A chr17 36719794 SRCIN1 rs118094989 C/A
chr6 39847207 DAAM2 rs139876341 A/G chr17 40714796 COASY rs200009135 G/C
chr6 43017728 CUL7 rs146808129 C/A chr17 48916935 WFIKKN2 rs35300894 G/A
chr6 83838955 DOPEY1 rs188246058 A/C chr17 55918596 MRPS23 rs117734846 C/T
chr6 160485490 IGF2R rs8191859 G/A chr17 73096776 SLC16A5 rs116126425 G/A
chr6 119628121 MAN1A1 NA C/T chr17 11461158 SHISA6 NA A/G
chr6 143825320 FUCA2 NA A/G chr17 12920199 ELAC2 rs140665334 G/A
chr6 34512160 SPDEF rs375427681 G/A chr17 14139300 CDRT15 rs11867613 A/G
chr6 34802049 UHRF1BP1 rs368713702 A/G chr17 14204942 HS3ST3B1 NA T/C
chr6 39893446 MOCS1 rs377167949 G/A chr17 26823582 SLC13A2 NA G/A
chr7 75617513 TMEM120A rs372363121 C/T chr17 2966032 OR1D5 rs2676564 C/G
chr7 141464509 TAS2R3 NA T/C chr17 5036211 USP6 rs201674756 C/T
chr7 144096938 NOBOX NA G/A chr17 74869016 MGAT5B NA G/A
chr7 148801869 ZNF425 NA C/G chr18 72913819 ZADH2 rs191356988 A/G
chr7 2689594 TTYH3 NA G/T chr18 44584631 KATNAL2 NA C/T
chr7 2962827 CARD11 rs3735133 G/A chr19 50028070 FCGRT rs374439544 C/T
chr8 8748876 MFHAS1 rs201875377 C/A chr19 54743747 LILRA6 rs10403230 C/G
chr8 17928855 ASAH1 rs11538152 G/A chr19 4504673 PLIN4 rs201143997 G/A
chr8 21766971 DOK2 rs202013016 G/A chr19 15730502 CYP4F8 rs61746468 C/T
chr8 42711517 RNF170 rs147488061 T/C chr19 15839677 OR10H2 NA T/C
chr8 107691450 OXR1 rs200863692 A/G chr19 18119274 ARRDC2 NA G/A
chr8 146067346 ZNF7 NA A/G chr19 22846981 ZNF492 NA A/C
chr8 52733228 PCMTD1 rs73592211 G/A chr19 40743901 AKT2 NA C/T
chr8 70541824 SULF1 NA C/T chr19 43420636 PSG6 rs370759098 G/A
chr9 2719083 KCNV2 rs143382624 G/C chr19 58370766 ZNF587 rs77577775 G/A
chr9 18776971 ADAMTSL1 rs117558542 G/A chr20 31685424 BPIFB4 NA T/C
chr9 19345978 DENND4C rs145052586 G/A chr21 33690064 URB1 rs145519835 C/T
chr9 84226764 TLE1 rs141959893 C/T chr21 37584306 DOPEY2 rs117132686 C/A
chr9 139750000 MAMDC4 rs200545888 T/C chr21 19666690 TMPRSS15 NA C/T
chr9 131670227 LRRC8A NA C/T chr22 22673302 IGLV5-52 NA C/T
chr10 25314128 THNSL1 rs78131600 C/T chr22 20127408 ZDHHC8 rs200408305 A/G
chr10 63810739 ARID5B rs201704836 G/A chr22 46725974 GTSE1 rs188655025 C/G
chr10 128192832 C10orf90 NA C/T chrX 2833605 ARSD rs111939179 C/T
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SNP, single nucleotide polymorphism; NA, not available.

We used OMIM database and GeneCards Database to further interpret these genes and found that 4 genes among the 162 genes might have relationship with the predisposition and/or oncogenesis of AD (Figure 4). To find the candidate mutations of atopic cataracts, we searched for the genes only in this patient without in his parents. We found 10 genes mutated in this patient only without in his parents (Table 2, Supplementary Table 2). Intriguingly, we compared these genes in this special patient with the patients those had been diagnosed with cataracts and had genes mutation, so as to discuss whether these 10 genes are belonging to this special kind of disease. After analyzing the available evidence, we found no data that may suggest these genes have been reported to correlate with cataracts. It is possible that these genes may uniquely belong to AD complicated with cataracts.

Figure 4. Gene prediction scores of the four genes and residual variation intolerance score of the genes.

Figure 4

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Table 2. List of 10 genes mutated in the patient without in his parents by whole exome sequencing.

Chromosome Position Gene SNP
chr12 11183066 TAS2R31 rs138895028 A/T
chr15 22473171 IGHV4OR15-8 NA A/G
chr17 16068287 NCOR1 rs201932638 A/T
chr19 33490566 RHPN2 rs74582927 T/C
chr1 16890607 NBPF1 rs200783506 G/A
chr22 22730788 IGLV5-45 NA G/A
chr22 22730800 IGLV5-45 rs114116194 A/C
chr2 90249202 IGKV1D-43 NA G/A
chr2 90249205 IGKV1D-43 NA A/C
chr5 140594470 PCDHB13 rs17844610 G/A
chr7 142149078 TRBV5-5 NA T/G
chr7 142149017 TRBV5-5 NA G/C
chr7 142149029 TRBV5-5 NA T/G
chr7 142149030 TRBV5-5 NA C/G
chr7 142149058 TRBV5-5 NA T/A
chr7 142149059 TRBV5-5 NA T/C
chr7 142149060 TRBV5-5 NA T/C
chr7 142149066 TRBV5-5 NA A/C
chr7 142149071 TRBV5-5 NA T/C
chr7 142149072 TRBV5-5 NA G/A
chr7 142149075 TRBV5-5 NA A/G
chr7 142149086 TRBV5-5 NA G/A
chr7 142149092 TRBV5-5 NA T/A
chr7 142149101 TRBV5-5 rs199978351 A/G
chr9 33385750 AQP7 rs114484742 C/T
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SNP, single nucleotide polymorphism; NA, not available.

DISCUSSION

Here, we presented a rare case of AD with cataract, and familial analysis by whole exome sequencing suggested that the pathogenesis of AD was related to genetic factors. Atopic cataract was firstly described in detail in 1936, where the author demonstrated the association of juvenile cataract with AD in 10 out of 101 AD patients, the mean age was 22 year-old, similar to our findings [5]. From 1940 to 1953, an ophthalmological check in 1,158 AD patients showed typical atopic cataract in 136 patients (11.7%) including 79 cases of visual disturbance [6]. To date, literatures describing cataracts in AD are mainly from Asian populations, including the Japanese population reporting the incidence of atopic cataracts around 10-15% [7], Filipino population [8] and Singapore population without Chinese population. Based on this, it seems that a greater interest may exist in Asians, or the prevalence and significance of this disease is greater in these populations. We firstly reported cataracts in a Chinese patient with AD with cataract. Interestingly, his father and his grandma are also AD patients.

It is known that cataract may develop as a result of aging, metabolic disorders, trauma, or heredity. Location of the cataract in the lens regulates visual acuity. There are two types of cataracts in AD patients in subcapsular region, anterior subcapsular cataracts (ASCs) and posterior subcapsular cataracts (PSCs). The literatures about ASCs or PSCs development in AD patients are inconsistent. Disease onset of ASCs is typically rapid, shieldlike bilateral visual impairment [4, 9], therefore, presentation of ASCs seems to be the “classic” cataract because ASCs in the absence of AD is not common [9]. On the contrary, some investigations showed that PSCs may be more common in AD patients [9–12]. In a 29 year-old male, AD presented with bilateral ASCs [13]. Histopathologic analysis of the ASCs tissues indicated a fibrous and amorphous mass, most likely extracellular matrix owing to the presence of irregularly arranged bundled strands of fibrils, typical of collagen. Lens epithelial cells (LECs) at the plaque were densely packed and myofibroblast-like and immunoreactive for alpha-smooth muscle actin. Similarly, a 6 year-old African American girl presented with an uncontrolled flare of AD, and her medical history was significant for asthma and allergic rhinitis with a family history of AD [14]. This was in agreement with our study that the male patient's father and grandmother were also AD. Our results showed that ASCs and PSCs were both existed in the left and right lens of the patient (Figure 2).

Although the pathogenesis of AD complicated with cataract has not been clearly elucidated, severe lesions of AD located over the face may be a critical factor in the development of atopic cataracts. In addition, AD complicated with cataracts may correlate with prolonged usage of corticosteroids and repetitive periorbital scratching [11]. Physical examination of the present patient showed a scratch on the face, neck, trunk, and four extremities, especially on the face and neck, suggesting that AD complicated with cataract in this patient may correlate with scratching. However, several studies reported that the presence of cataracts (both ASCs and PSCs) were not correlated with the disease onset, severity, or duration of AD [15, 16], and the clinical features of AD patients who developed cataracts were similar to the patients who did not have. It is notable that cataract was seen in some patients with only mild facial involvement [16, 17]. On the other hand, systemic corticosteroids are known to cause ocular complications. It is reported that incidence of cataract is dose and treatment duration dependent, where the patients received the equivalent of prednisone, 10 to 15 mg/d for at least 1 year displayed the greatest risk [18]. However, Niwa, et al discussed the incidence of cataract among 3 groups of AD patients [11]. The patients were treated with topical corticosteroids, or treated with both topical and systemic corticosteroids, or corticosteroid-naive patients, respectively. The authors found no difference among these groups. Interestingly, there are 37 patients developed cataract, by which 86% showed posterior cataract [11]. This finding was similar to our study, where the patient had no history of corticosteroids. Tatham, et al reported two boys about 10 year-old diagnosed with widespread AD of the face, neck, trunk and limbs. After diagnosis and treatment with topical steroids for 2 years, both of them complained of gradual onset of blurred vision in both eyes, ophtalmic testing found PSCs in these patients, suggesting that AD and topical corticosteroids may be associated with cataracts in children [19]. Together, whether usage of corticosteroids and scratching may be susceptible factors to AD complicated with cataract is still needed to be clarified in the future with large scales of patients.

Genetic epidemiologic studies on monozygotic twins [20], and genetic association studies indicated a genetic susceptibility for AD [21]. In the present study, four genes including CORIN, CARD11, MMP2, DNASE1L, which were previously reported to be risk factors for AD [22–25], were also mutated in this patient and his father. CARD11 encodes CARMA1, an essential scaffold protein for lymphocyte activation via T cell receptor and B cell receptor signaling [26]. CARMA1 plays important roles in T cell differentiation, regulation of JunB, GATA3 and the subsequent generation of Th2 cell specific cytokines [27]. Mice that are homozygous for the mutation affecting CARMA1 showed gradual development of AD with high level of serum IgE [28]. Li, et al [29] showed that chronic loss of epidermal caspase-8 recapitulates many aspects of AD, such as a spongiotic phenotype whereby intercellular adhesion between epidermal keratinocytes is disrupted, adversely affecting tissue architecture and function. However, subcutaneous injection of matrix metalloproteinase-2 (MMP2) inhibitor strongly down-regulated the intercellular space found in the suprabasal layers of the epidermis [29]. Suppression of MMP2 also restored full length E-cadherin to normal levels and significantly decreased the amount of the cleaved E-cadherin C-terminal fragments product. Transepidermal water loss through the epidermis from caspase-8 conditional knockout mice treated with the MMP2 inhibitor was strongly reduced relative to controls, suggesting that suppression of MMP2 is able to abrogate the effect of caspase-8 knockout induced AD. In a whole exome sequencing study of early-onset AD from a Korean population, Heo, et al discussed family-specific candidate genetic variants from three separate families, and validated the possible genes in 112 AD patients and 61 controls. Results showed that three variants of the COL6A6 gene appeared in all three families and were in close proximity to AD related loci on chromosome 3q21 [30]. The homozygous frequency for the rs16830494 minor allele (AA) and the rs59021909 (TT) allele and the rs200963433 heterozygous (CT) frequency were all higher in AD cases compared to controls, suggesting that COL6A6 variants may be risk factors for AD.

Matsuda, et al [7] discovered that -56 T allele in the IFNGR1 promoter was significantly associated with an increased risk of ocular AD, especially of atopic cataracts. In our study, the whole exome sequencing revealed the -56 CT genotype in both the patient and his father, which contained -56 T allele, whereas his mother harbored -56 CC genotype. The IFNGR1 gene promoter construct that contained the -56 T allele showed higher transcriptional activity in LECs than did the construct with the -56 C allele after stimulation with IFN-γ, and there was higher IFNGR1 expression in the LECs in atopic than in senile cataracts [7], indicating that the -56 T allele in the IFNGR1 promoter leads to elevated IFNGR1 transcriptional activity and represents a genetic risk factor for atopic cataracts. Hori, et al [25] investigated the role of PAI-1, IFN-γ downstream molecule in the pathogenesis of atopic cataracts. They found that the IFN-γ, PAI-1 and TGF-β1 were involved in the pathophysiology of atopic cataracts.

According to the OMIM database and GeneCards Database, we found 4 genes including CARD11, PIK3CD, LILRB3, C8B, may correlate with the pathogenesis of AD. Among them, CARD11 had been reported to have relation with AD [24]. Phenolyzer were used to examine the association of these candidate genes with AD and we found that PIK3CD, LILRB3, C8B were in the same biosystem with CARD11 in the record of NCBI's Biosystem. According to the result of residual variation intolerance score (RVIS) [31], CARD11 had a RVIS score of-1.39 and a percentile of 4.33%, showing that it was amongst the 4.33% most intolerant of human gene (FDR = 1.87×10-6), and PIK3CD, the 2.72% most intolerant human gene (FDR = 8.11×10-6), had a score of -1.66, while LILRB3 and C8B with positive scores had more common functional variation. The normalized RVIS of CARD11 and PIK3CD was approximated to 1, indicating that these two genes were considered as “intolerant”. PIK3CD had a HI score of 0.607 [32], suggesting that haploinsufficiency of the PIK3CD gene may associate with the pathogenesis of AD (Figure 4).

In conclusion, this is the first report of familial AD with cataracts, and the family-based whole exome sequencing found that 162 genes were both mutated in the young patient and his father, while 10 genes were only mutated in the young patient of AD complicated with cataracts. Further studies with large scale need to discuss the functional role of these genes in AD, especially in AD complicated with cataracts.

MATERIALS AND METHODS

Subjects

There was a 19 year-old young male with AD accompanied with cataracts. His father was AD patient, while his mother was not AD or cataracts patient. All of them were recruited in this study. The grandma was also AD, because of impossibility, the grandma was not included. Patients were collected from the Department of Dermatology of the West China Hospital Sichuan University. AD patients met the diagnostic criteria of Hanifin and Rajka [33]. Data about demographic and clinical features were collected from hospital records or by questionnaire and reviewed by experienced physicians. All subjects gave their written consent to participate before study. This study was approved by the ethics committee of the Sichuan University.

DNA extraction and whole exome sequencing

EDTA anti-coagulated venous blood (10ml) was collected from the young male and his parents. The genomic DNA was extracted using the TIANamp Genomic DNA Kit (Tiangen Biotech, Beijing, China) following the manufacturer's protocol. Whole exome enrichment was performed using Agilent SureSelect Human All Exon Kit 50M (Agilent Technologies, Santa Clara, CA, USA) and sequenced with the Illumina HiSeq 4000 System (HiSeq® 3000/4000 SBS Kit).

Sequence alignment, variant calling, and annotation

The sequenced reads were aligned to the hg19 human reference genome sequence using BWA aln and BWA sampe, and removed PCR duplicates with PICARD. Variations were called by GATK HaplotypeCaller with default parameters, after calling genotyping were jointed together by GATK CombineGVCFs/GenotypeGVCFs. Variants were retained considering reads depth DP>= 8, MQ >=20. Beyond that, variants were annotated by ANNOVAR, filtered by position (non-synonymous or gain/loss of stops), VAF < 0.005 (1000 genome project (2012) and HAPMAP), potential damaging effect (variants that were predicted as damaging variants by at least 2 databases, including SIFT, PolyPhen2 HDIV, PolyPhen2 HVAR, LRT, MutationTaste, MutationAssessor, FATHMM, GERP++, PhyloP and SiPhy).

SUPPLEMENTARY MATERIALS TABLES

Footnotes

CONFLICTS OF INTEREST

The authors report no declarations of interest.

GRANT SUPPORT

This work was supported by grants from the National Natural Science Foundation of China (81372504 and 81241068).

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