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Exome Sequencing Trio Analysis Essay

tag."); } tt_db = null; return false; } function tt_MkMainDiv() { // Create the tooltip DIV if(tt_body.insertAdjacentHTML) tt_body.insertAdjacentHTML("afterBegin", tt_MkMainDivHtm()); else if(typeof tt_body.innerHTML != tt_u && document.createElement && tt_body.appendChild) tt_body.appendChild(tt_MkMainDivDom()); // FireFox Alzheimer bug if(window.tt_GetMainDivRefs && tt_GetMainDivRefs()) return true; tt_db = null; return false; } function tt_MkMainDivHtm() { return('' + (tt_ie56 ? 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Sequential Trio Whole Exome Sequencing
Test Information:Indications for Testing
Patient with a suspected genetic syndrome but no definitive diagnosis by proband only exome sequencing previously performed in our laboratory using version 3 exome reagents.

The sequential Trio Whole Exome Sequencing (sequential trio WES) test is ordered by a physician and must be accompanied with a consent form and detailed clinical information. In general, the test is used when a physician decides that a patient's previous proband only exome (test code 1500) did not yield a definitive diagnosis and chooses to order sequential trio WES in an effort to obtain additional information such as de novo or compound heterozygous changes in the proband to help with the molecular diagnosis.

Note: This test is only available for patients who were previously tested for proband only exome in our laboratory using version 3 exome reagents as indicated in the title section on the patient's proband exome report. No further exome testing in the wet lab is needed for the patient, the previous exome data will used for analysis. Exome sequencing of parents are required to interpret trio WES results (test code 1551 for parental samples, see requisition form). See below and requisition for sample requirements and further details. Testing cannot be requested unless both parents submit samples for testing. If parental samples have previously been submitted please call client services to determine if new sample is required.
Test Details
Test Code:1601
Special Notes: The sequential trio Whole Exome Sequencing test is a highly complex test that is newly developed for the identification of changes in a patient's DNA that are causative or related to their medical concerns. In contrast to current sequencing tests that analyze one gene or small groups of related genes at a time, the Trio Whole Exome Sequencing test will analyze the exons or coding regions of thousands of genes simultaneously using next-generation sequencing techniques.

The principle of the test is to sequence nucleotide by nucleotide, the human exome of an individual to a depth of coverage necessary to build a consensus sequence with high accuracy. This consensus sequence is then compared to standards and references and the parental WES data and the result is interpreted by board-certified laboratory directors and clinicians. By sequencing the exome of a patient and their parents and then comparing it to normal reference sequence, variations in an individual's DNA sequence can be identified and related back to the individual's medical concerns in an effort to discover the cause of the medical disorder.

For information on specific coverage, please click here: Whole Exome Sequencing Version 3 Coverage Search Tool

This test is only available for patients who were previously tested for proband only exome in our laboratory using version 3 exome reagents as indicated in the title section on the patient's proband exome report.
Technical Information
Methodology:Exome Capture and Next Generation Sequencing
Sample & Shipping Information
Test Requisition:Please call client services at 1-800-411-4636 to obtain requisition.
Specimen Type:Blood
Requirements:Additional sample from the proband is not needed. For the parental samples draw blood in an EDTA (purple-top) tube(s) for both parents. Send at least 10cc (adults).
Shipping Conditions:Ship at room temperature in an insulated container by overnight courier. Do not heat or freeze. Sample must arrive within 72 hrs.

Specimen Type:Purified DNA
Requirements:Additional sample from the proband is not needed. For the parental samples send at least 20ug of purified DNA (minimal concentration of 50ng/uL; A260/A280 of ~1.7) for both parents.
Shipping Conditions:Ship at room temperature in an insulated container by overnight courier. Do not heat or freeze.

Turn Around Time:8 weeks
Billing Information
List Price: *For Insurance or Institutional Prices, please call.
CPT Codes:81416x2

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.

Myopia is the most common ocular disease, with an increasing global prevalence, especially in East Asia (1⇓–3). Uncorrected myopia is the leading cause of vision impairment worldwide, according to a report by the World Health Organization (4). High myopia (HM) is very severe myopia, which is defined as less than or equal to −6.00 diopters (D) (5). HM is clinically associated with severe ocular complications, such as macular degeneration, retinal detachment, cataract, and glaucoma, which make HM the leading cause of irreversible blindness in East Asia (1, 6).

Myopia is etiologically heterogeneous because both environmental factors and genetic factors are involved (1, 7). Epidemiological surveys show that outdoor activity reduces the prevalence of myopia, decreasing the risk of myopia associated with short-distance work (8, 9). Myopia often exhibits apparent familial aggregation (10⇓–12), and the number of myopic parents is significantly correlated with myopic onset and progression in children (13). Twin studies and population-based epidemiological investigations show that genetic factors significantly contribute to the development of myopia (6, 14, 15), particularly HM (5). Genome-wide association studies (GWAS) and subsequent metaanalyses have identified dozens of loci and genes that are associated with general myopia or HM (16, 17). Of note, the identified genetic contributions of the dozens of loci and genes to myopia are very limited. To date, based on pedigree studies with next-generation sequencing, several disease-causing genes have been discovered, including two recessive genes, LRPAP1 (18) and LEPREL1 (19); four dominant genes, ZNF644 (20), SCO2 (21), SLC39A5 (22), and P4HA2 (23); and one X-linked gene, ARR3 (24). However, a large-scale screening of these genes in HM cohorts provided evidence that only a small proportion (<5%) of HM patients harbor mutations in these known genes, which can be attributed to as-yet-unidentified causative genes (25).

Because preschool children encounter fewer risks from environmental pressures, we proposed that the condition of early-onset high myopia (EOHM) is driven by a genetic predisposition more than by environmental factors. In this study, we recruited 18 familial trios (healthy parents and an EOHM child) to decipher the genetic predisposition using whole-exome sequencing (WES). We identified a cluster of unique genes linked to EOHM, as well as mutations in the reported genes. Notably, we showed that both rare inherited mutations and de novo mutations significantly contributed to EOHM. Expression profiling in ocular tissues and mutant mouse phenotyping demonstrated the pathogenicity of the mutations in a unique gene, BSG. Our results provide insights into the genetic basis and molecular mechanisms of childhood HM.


EOHM Samples and WES.

In this study, we recruited a cohort of 54 individuals, including 18 children with EOHM and their unaffected parents. The ages at examination of all probands were less than 6, indicating EOHM. The refraction of each patient was less than or equal to −6.00 diopters (D) (Table S1).

WES was performed for all probands and the parents of the 18 trios to investigate the genetic basis. Burrows–Wheeler transform (26) and Genome Analysis Toolkit (GATK) (27) were used for the data analyses. The detailed statistical information of the WES data from the 18 HM trios is summarized in the Table S2.

Table S1.

The clinical information of 18 probands

Table S2.

Detailed statistic information of the WES data from the 18 HM trios

Rare Inherited Mutations in EOHM.

Rare inherited mutations cause HM in an autosomal recessive, dominant, or X-linked manner. Based on the sporadic EOHM patients used in this study, we first tried to identify biallelic mutations using mirTrios (28). We identified two known HM candidate genes (LEPREL1 and GRM6), three oculopathy-related genes (FAM161A, GLA, and CACNA1F), and a further possible gene (MAOA) in six different individuals, which accounted for one-third of the EOHM samples (Dataset S1 and Table S3).

In proband H16, we detected a damaging biallelic mutation (p.L530P) in LEPREL1, which is involved in collagen chain assembly, stability, and cross-linking. Mutations in this gene have been reported in patients with HM in western Asia (19, 29) and China (30). Leprel1 knockout (KO) mice with abnormal collagen chemistry partially recapitulate the myopic changes (31). Proband H33 carries a homozygous mutation (p.Q708H) in the GRM6 gene. Mutations in GRM6 are reported in HM (32) and nyctalopia (33). In addition to these two known genes, we identified a unique candidate gene, FAM161A, which is involved in microtubule stabilization (34, 35). Proband H45 harbors a nonsense mutation (p.Q302X) in FAM161A. Loss-of-function mutations in this gene are reported to cause autosomal recessive retinitis pigmentosa (36, 37). Interestingly, HM is coupled with these diseases in patients (38).

In another three unrelated patients, we detected mutations in three candidate genes, including MAOA, GLA, and CACNA1F. A boy (H1) harbored a hemizygous mutation in MAOA (p.V18E), which encodes an oxidative deaminase for amines. It is reported that 5-hydroxytryptamine is involved in the development of retinal ganglion cells (39, 40). In addition, we identified a hemizygous mutation (p.Y216F) in the galactosidase α (GLA) gene in proband H9. This gene is a known candidate gene for Fabry disease with an ocular pathology (41) and corneal dystrophy (42). Furthermore, a hemizygous mutation in the CACNA1F gene (p.R1060W) was discovered in proband H29. CACNA1F mutations are reported in patients with HM, congenital stationary night blindness type 2A (43), cone–rod dystrophy (44), and nyctalopia (45).

Table S3.

Summary of identified variations associated with HM

Contribution of the de Novo Mutation to EOHM.

With the exception of the rare inherited mutations described above, we propose that de novo germline mutations may contribute to the genetic architecture of EOHM, which has not been fully studied. Using the Burrows–Wheeler Aligner (BWA)/GATK/mirTrios, we identified a total of 29 de novo single-nucleotide variants (SNVs) within the coding regions. We confirmed that 20 of the 29 de novo SNVs were genuine de novo mutations by direct PCR sequencing, and 17 were identified as nonsynonymous mutations (Dataset S2). Overall, 13 of the 18 probands (72%) carried at least one de novo mutation, and 7 probands harbored (39%) more than two de novo mutations.

The overall de novo mutation rate in the probands (1.11 events per proband on average) was consistent with a background de novo mutation rate of ∼0.91–1.07 that was estimated from previous studies (46⇓–48). To determine whether the EOHM probands had elevated de novo mutations compared with the controls, we obtained the de novo mutation rates in the normal individuals from the NPdenovo database (49). As a result, we found an increased trend of the overall de novo mutation rate in the HM patients (1.11 events per proband on average) compared with that in the normal individuals (0.74 events per individual on average) with an HM/control rate ratio (RR) of 1.51 (P = 0.05) (Fig. 1A). Interestingly, we observed a significantly elevated de novo missense mutation rate in the patients compared with that in the normal individuals (RR = 1.98, 0.94 vs. 0.48, P = 0.008), and this difference was even greater (RR = 3.74, 0.39 vs. 0.1, P = 0.004) when only the damaging de novo missense mutations were considered. In addition, the number of de novo SNVs in each proband was significantly correlated with the paternal age (r = 0.491, P = 0.019) (Fig. 1B) using a Pearson correlation analysis, which is consistent with previous findings (50, 51). We correlated the number of de novo mutations detected and the degree of myopic refraction in each eye to analyze the possible direct contributions of the de novo mutations to the HM phenotypes. We observed a trend of a higher degree of myopia as the number of de novo mutations increased (0, one, and two) (Fig. 1 C and D).

Fig. 1.

Patterns of de novo mutations in HM patients and their contribution to disease risk. (A) Plot of the mean de novo mutation rate of HM patients (HM) and normal individuals (control). The de novo mutation rate for normal individuals was calculated based on 982 normal individuals from the NPdenovo database (www.wzgenomics.cn/NPdenovo/). The statistical significance of the differences in the de novo mutation rates between the HM patients and the controls was tested using a two-sample Poisson rate test. (B) The relationship between the number of de novo mutations and the paternal age. (C) The relationship between the number of de novo mutations in the proband and the diopter sphere–oculus dexter (DS-OD). (D) The relationship between the number of de novo mutations in the proband and the diopter sphere–oculus sinister (DS-OS). (E) A scatter diagram of the total damaging scores and the expected de novo mutation rate (expected DNMR) of the genes with de novo mutations. The total damaging score was calculated by 14 generic functional prediction tools, and the expected DNMR was used for each gene DNMR average from the mirDNMR database (www.wzgenomics.cn/mirdnmr/).

Candidate Genes with Damaging de Novo Mutations.

The detection of recurrent de novo mutations is a commonly used method to identify disease-causing genes. However, in this study, we found that the de novo mutations occurred in different genes in all cases, which prevented us from performing a statistical analysis of any of the specific genes. Therefore, we used 14 bioinformatics tools to predict the damaging effects of all missense de novo mutations detected and identified mutations that were more likely to confer a disease risk (Fig. 1E). One de novo missense mutation in the EPHB2 gene was identified in proband H42, and the mutation was predicted to be damaging by 10 bioinformatics tools. The EPHB2 gene is involved in retinal axon projections via interactions with ephrin-B proteins (52). In addition, it was reported that the growth cone collapse and axon retraction of retinal ganglion cells could be induced by EPHB2 gene expression (53). Therefore, the direct evidence of the contribution of the EPHB2 gene to retinal axon projections suggests that the EPHB2 mutations may be a possible cause of the optical problems observed in the proband. One de novo missense mutation in the CSMD1 gene was identified in proband H70, which is related to several neuron function-related disorders, such as schizophrenia, autism, sclerosis, etc. (54). One de novo missense mutation in the TENM4 gene was identified in proband H1. Notably, the TENM4 gene is also associated with neuron function-related disorders based on the genome sequencing of cases and controls (55) and a GWAS study (56). In addition, the TENM4 gene is essential for embryonic mesoderm development in mouse model studies (57). One de novo missense mutation in the BSG gene was identified in proband H13. The BSG gene encodes a photoreceptor-specific transmembrane protein, Basigin, which cross talks with rod-derived cone viability factor (RdCVF) (58, 59). The BSG gene will be discussed further in the subsequent sections as a unique candidate gene for EOHM.

Expanded Screening Identified BSG Mutations.

A mutation in the BSG gene (c.889G>A, p.G297S) identified in the EOHM patient (Fig. 2) showed strong pathogenicity, according to computational predictions. Moreover, it is completely absent in Exome Variant Server (EVS) and 1000 Genomes Project (1000G) and exhibits a very rare frequency in Exome Aggregation Consortium (ExAC) (1/115742, 8.64e-06). We further screened the entire coding region of the BSG gene in a large cohort of 1,040 unrelated patients with HM, none of which had mutations in the known genes, to determine the replication of the BSG mutations. Interestingly, we also identified one different missense mutation (c.661C>T, p.P221S), one nonsense mutation (c.205C>T, p.Q69X), and one splicing mutation (c.415+1G>A) in the BSG gene (Table 1 and Fig. 2) in a total of four unrelated families. All of these mutations were absent in the ExAC database and either led to a protein coding change (c.205C>T, p.Q69X; c.415+1G>A) or displayed strong pathogenicity according to the computational assessment (c.889G>A, p.G297S; c.661C>T, p.P221S). Furthermore, both of the missense mutation (G297S and P221S) sites are located in highly conserved amino acids across different species (Fig. 2). However, because the parental DNA was unavailable, it is not clear whether these mutations are de novo mutations. Taken together, these results confirmed the recurrence of the BSG mutations by expanded screening in an additional HM cohort, which supported the pathogenicity of this gene for HM.

Fig. 2.

Identification of mutations in the BSG gene. (A) Identification of mutations in the BSG gene in five unrelated patients. (B) Schematic of the BSG gene and its domains with the sites of the variants identified in this study. (C) Both missense mutations (G297S and P221S) are located in highly conserved regions.

Table 1.

Summary of BSG mutations and the associated phenotypes identified in this study

Bsg Mutant Mice Display Typical Myopic Phenotypes in the Axial Length.

We generated knockin mice (Fig. S1) with a c.901G>A mutation corresponding to the c.889G>A mutation identified in the EOHM patient to further investigate the functional impact of the BSG mutation. The total axial length (AL) and vitreous chamber depth (VCD) were measured in variant ages (4, 6, 8, and 10 wk) of the mutant mice and wild-type (WT) siblings. The results showed that the ΔAL significantly changed with group (F = 51.26, P = 1.63e-10) and time (F = 42.36, P = 6.50e-14) overall, and there were no interactions between group and time (F = 2.35, P = 0.1012) (Fig. 3). The heterozygous mutant group had an increased AL in the subsequent 2 wk compared with the WT group (Tukey multiple comparison, Δmean = 0.015 mm, P < 1e-50). The ΔAL in the subsequent 2 wk also changed with time (peaks at 6 wk, and then the ΔAL decreased slightly). However, there were no significant differences with group (F = 0.47, P = 0.49) and time (F = 1.86, P = 0.16) in ΔVCD (Fig. S2). The trend of the AL and VCD of the WT mice was consistent with the previous studies as follows: AL increases during postnatal development, whereas the VCD decreases (60, 61).

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