Microphthalmia, Anophthalmia and Anterior Segment Dysgenesis Panel

Last modified: Mar 21, 2018


  • Is a 54 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion / diagnosis of microphthalmia, anophthalmia or an anterior segment dysgenesis disorder.

Analysis methods

  • PLUS
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81406
SEQ 81407
SEQ 81408
DEL/DUP 81479


The Blueprint Genetics Microphthalmia, Anophthalmia and Anterior Segment Dysgenesis Panel (test code OP0601):

  • Is a 54 gene panel that includes assessment of selected non-coding disease-causing variants
  • Assesses for non-coding disease-causing variants in one or more genes. For additional information, see the list of genes included in this panel.

  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

Test Specific Strength

Assesses for non-coding disease-causing variants in one or more genes. For additional information, see the list of genes included in this panel.

ICD codes

Commonly used ICD-10 code(s) when ordering the Microphthalmia, Anophthalmia and Anterior Segment Dysgenesis Panel

ICD-10 Disease
Q11.0 Anophthalmia
Q11.2 Microphthalmia

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Anophthalmia and microphthalmia are rare developmental defects of the globe. Microphthalmia refers to an eye with reduced volume and may be associated with coloboma or with an orbital cyst. Anophthalmia is the absence of one or both eyes. Anophthalmia and microphthalmia may be unilateral or bilateral, and over 50% are associated with systemic abnormalities. Anophthalmia and microphthalmia may be inherited as an autosomal dominant, autosomal recessive, or X-linked manner. The major causative gene is SOX2 in which heterozygous loss-of-function variants account for 25% of cases. Examples of syndromes associated with anophthalmia/microphthalmia are CHARGE syndrome (CDH7) and COFS syndrome (ERCC2ERCC5ERCC6). Anterior segment dysgenesis (ASD) disorders encompass a wide variety of developmental conditions affecting the cornea, iris, and lens. It can be an isolated ocular anomaly or accompanied by systemic defects. Anterior segment anomalies are associated with an approximate 50% risk of glaucoma. The majority of genes associated with ASD show autosomal dominant inheritance. Axenfeld-Rieger syndrome is caused by variants in PITX2 and FOXC1 with an estimated prevalence of 1:200,000.

Genes in the Microphthalmia, Anophthalmia and Anterior Segment Dysgenesis Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCB6 Blood group, Langereis system, Pseudohyperkalemia AD/BG 9 19
ADAMTS18 Knobloch syndrome 2, Microcornea, myopic chorioretinal atrophy, and telecanthus, Retinal dystrophy, early onset, autosomal recessive AR 4 11
ALDH1A3 Microphthalmia, isolated 8 AR 6 23
BCOR Microphthalmia, syndromic, Oculofaciocardiodental syndrome XL 29 48
BMP4 Microphthalmia, syndromic, Orofacial cleft AD 9 34
BMP7 Anophthalmia, microphthalmia, and variable brain, ear, palate, and skeletal anomalies AD 1 5
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 192 784
COL4A1 Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease AD 46 97
COX7B Linear skin defects with multiple congenital anomalies 2 XL 4 3
CYP1B1 Glaucoma, primary open angle glaucoma, juvenile-onset, Glaucoma, primary open angle, adult-onset, Glaucoma, primary congenital, Peters anomaly AR 19 236
ERCC2 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive AR 22 86
ERCC5 Xeroderma pigmentosum, Xeroderma pigmentosum/Cockayne syndrome AR 18 51
ERCC6* Xeroderma Pigmentosum-Cockayne Syndrome, De Sanctis-Cacchione syndrome AD/AR 45 92
FOXC1 Axenfeld-Rieger syndrome, Iridogoniodysgenesis, Peters anomaly AD 35 133
FOXE3 Aphakia, congenital primary, Anterior segment mesenchymal dysgenesis AR/AD 7 23
FOXL2 Premature ovarian failure, Blepharophimosis, epicanthus inversus, and ptosis AD 71 209
FRAS1 Fraser syndrome AR 24 51
FREM1 Bifid nose, Manitoba oculotrichoanal syndrome, Trigonocephaly AD/AR 12 33
FREM2 Fraser syndrome 2 AR 4 17
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD/AR 28 105
GRIP1 Fraser syndrome AR 5 17
HCCS Linear skin defects with multiple congenital anomalies 1 (MIDAS syndrome) XL 6 13
HESX1 Septooptic dysplasia, Pituitary hormone deficiency, combined AR/AD 11 26
HMX1 Oculoauricular syndrome AR 3 2
MAB21L2 Microphthalmia/coloboma and skeletal dysplasia syndrome AR 5 7
MFRP Microphthalmia, isolated 5, Nanophthalmos 2, Retinitis pigmentosa, autosomal recessive AR 18 29
MITF Renal cell carcinoma with or without malignant melanoma, Tietz albinism-deafness syndrome, Waardenburg syndrome, Melanoma, cutaneous malignant AD 24 55
NAA10 Microphthalmia, syndromic 1 (Lenz microphthalmia) XL 14 9
NDP Exudative vitreoretinopathy, Norrie disease XL 29 159
OCRL Lowe syndrome, Dent disease XL 38 258
OTX2 Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction AD 17 65
PAX2 Isolated renal hypoplasia, Papillorenal syndrome AD 23 88
PAX6 Aniridia, cerebellar ataxia, and mental retardation (Gillespie syndrome), Keratitis, Coloboma, ocular, Cataract with late-onset corneal dystrophy, Morning glory disc anomaly, Foveal hypoplasia, Aniridia, Optic nerve hypoplasia, Peters anomaly AD 106 473
PITX2 Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly AD 19 95
PQBP1 Renpenning syndrome XL 12 18
PRSS56 Microphthalmia, isolated 6 AR 10 23
PXDN Anterior segment dysgenesis 7 AR 6 10
RAB3GAP1 Warburg micro syndrome AR 17 62
RARB Microphthalmia, syndromic 12 AD/AR 8 6
RAX Microphthalmia, isolated 3 AR 4 13
RBP4 Retinol dystrophy, iris coloboma, and comedogenic acne syndrome AR 6 6
SHH Holoprosencephaly, Microphthalmia with coloboma AD 35 216
SIX3 Holoprosencephaly AD 12 83
SIX6 Microphthalmia, isolated, with cataract 2, Optic disc anomalies with retinal and/or macular dystrophy AD 2 6
SLC38A8 Foveal hypoplasia 2 AR 11 11
SMCHD1 Facioscapulohumeral muscular dystrophy Digenic (involving a SMCHD1 mutation and permissive D4Z4 haplotype) 37 71
SMOC1 Microphthalmia with limb anomalies AR 4 13
SOX2* Microphthalmia, syndromic AD 25 99
STRA6 Microphthalmia, syndromic, Microphthalmia, isolated, with coloboma AR 19 31
TENM3 Microphthalmia, isolated, with coloboma 9 AR 7 2
TFAP2A Branchiooculofacial sydrome AD 9 41
VPS13B Cohen syndrome AR 231 197
VSX2 Microphthalmia, isolated 2, Microphthalmia, isolated, with coloboma 3 AR 8 13
ZIC2 Holoprosencephaly AD 16 112

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
CHD7 Chr8:61734568 c.2836-15C>G NM_017780.3
CHD7 Chr8:61757794 c.5051-15T>A NM_017780.3
CHD7 Chr8:61763035 c.5405-17G>A NM_017780.3 rs794727423
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
COL4A1 Chr13:110802678 c.*32G>T NM_001845.4
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
CYP1B1 Chr2:38303243 c.-322A>C NM_000104.3
ERCC6 Chr10:50681659 c.2599-26A>G NM_000124.3 rs4253196
FOXC1 Chr6:1613076 c.*734A>T NM_001453.2 rs35717904
FOXL2 Chr3:138663815 c.*619C>A NM_023067.3 rs180829214
NDP ChrX:43818099 c.-207-1G>A NM_000266.3
NDP ChrX:43832549 c.-208+1G>A NM_000266.3
NDP ChrX:43832548 c.-208+2T>G NM_000266.3
NDP ChrX:43832545 c.-208+5G>A NM_000266.3
OCRL ChrX:128687279 c.239-4023A>G NM_000276.3
OCRL ChrX:128674707 c.40-14A>G NM_000276.3
OCRL ChrX:128696350 c.940-11G>A NM_000276.3
PAX6 Chr11:31685945 c.*125537G>T NM_000280.4 rs606231388
PAX6 Chr11:31828474 c.-128-1G>T NM_000280.4
PAX6 Chr11:31832374 c.-129+2T>A NM_000280.4
PAX6 Chr11:31828396 c.-52+1G>A NM_000280.4
PAX6 Chr11:31816377 c.524-41T>G NM_000280.4
PITX2 Chr4:111539855 c.412-11A>G NM_000325.5
SHH Chr7:156061506 c.-456690G>A NM_000193.2
SHH Chr7:156583831 c.-979015A>G NM_000193.2 rs606231150
SHH Chr7:156583949 c.-979133C>G NM_000193.2 rs606231151
SHH Chr7:156583951 c.-979135C>T NM_000193.2
SHH Chr7:156584107 c.-979291T>G NM_000193.2
SHH Chr7:156584153 c.-979337A>G NM_000193.2
SHH Chr7:156584164 c.-979348A>G NM_000193.2
SHH Chr7:156584166 c.-979350G>A NM_000193.2 rs606231147
SHH Chr7:156584166 c.-979350G>C/T NM_000193.2
SHH Chr7:156584168 c.-979352C>T NM_000193.2 rs587779752
SHH Chr7:156584241 c.-979425T>C NM_000193.2 rs606231149
SHH Chr7:156584265 c.-979449A>T NM_000193.2 rs606231148
SHH Chr7:156584275 c.-979459T>C NM_000193.2 rs606231152
SHH Chr7:156584283 c.-979467C>A NM_000193.2
SHH Chr7:156584465 c.-979649C>G NM_000193.2 rs606231146
SHH Chr7:156584863 c.-980047C>T NM_000193.2
SHH Chr7:155599270 c.301-19G>A NM_000193.2
SMCHD1 Chr18:2701019 c.1647+103A>G NM_015295.2
ZIC2 Chr13:100634295 c.-24C>T NM_007129.3

Added and removed genes from the panel

Genes added Genes removed

Test strength

Assesses for non-coding disease-causing variants in one or more genes. For additional information, see the list of genes included in this panel.

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

Due to one or more regions of segmental duplication, this panel has reduced sensitivity to detect variants in exon 1 of GJA1 and exon 1 of SOX2. Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics microphthalmia, anophthalmia and anterior segment dysgenesis panel covers classical genes associated with COFS syndrome, CHARGE syndrome, Axenfeld-Rieger syndrome, anophthalmia, anterior segment dysgenesis disorder, isolated anophthalmia - microphthalmia, microphthalmia, Peters anomaly and septo-optic dysplasia. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%


The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.