3-M Syndrome / Primordial Dwarfism Panel

Summary
  • Is a 24 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of primordial dwarfism including 3-M syndrome, Jawad syndrome and Meier-Gorlin syndrome microcephalic primordial dwarfism disorders (mopd, Seckel syndrome or short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome). The genes on this panel are included in the Comprehensive Short Stature Panel and the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

24

Test code

MA2401

Panel size

Small

CPT codes
81479

Summary

The Blueprint Genetics 3-M Syndrome / Primordial Dwarfism Panel (test code MA2401):

ICD codes

Commonly used ICD-10 code(s) when ordering the 3-M Syndrome / Primordial Dwarfism Panel

ICD-10 Disease
Q87.1 3-M syndrome
Q87.1 Microcephalic primordial dwarfism disorders (mopd)
Q87.1 Seckel syndrome
Q87.1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome)
Q87.1 Jawad syndrome
Q87.1 Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)

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. Read more about our sample requirements here.

The clinical phenotypes of the disorders covered by this panel range in the severity of growth retardation and microcephaly, as well as in the degree of intellectual disability, but there can be significant clinical overlap among syndromes. Intellect is intact in most cases of microcephalic osteodysplastic primordial dwarfism type II (MOPD II) and Meier-Gorlin syndrome, whereas Seckel syndrome is classically characterized by substantial intellectual disability. The genetic bases of many of these disorders have been elucidated recently, and the implicated genes have been shown to be vital for fundamental biological processes, such as DNA replication and damage repair. Microcephalic primordial dwarfism constitutes a group of disorders characterized by severe pre- and postnatal growth retriction accompanied by microcephaly. These disorders include MOPD I (Taybi-Linder syndrome), II and III, various types of Seckel syndrome and Meier-Gorlin syndrome. Altogether 150 published cases of type I, II and III MOPD have been reported in the literature. 3-M syndrome is characterized by prenatal growth restriction in the absence of recognizable maternal or placental pathology and by the failure of postnatal catch-up growth resulting in significant proportionate short stature. It is estimated that 77.5% of 3-M syndrome is attributed to mutations in the CUL7 gene, 16% to mutations in OBSL1 gene and less than 5% to mutations in CCDC8 gene. This panel also includes other genes causing syndromes with prenatal-onset growth retardation.

Genes in the 3-M Syndrome / Primordial Dwarfism Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 10 33
BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1 AR 42 37
CCDC8 Three M syndrome 3 AR 2 3
CDC45 Meier-Gorlin syndrome 7 AR 10 19
CDC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 2 2
CDT1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 6 12
CENPJ Seckel syndrome, Microcephaly AR 34 9
CEP152 Seckel syndrome, Microcephaly AR 20 20
CEP63 Seckel syndrome AR 7 2
CUL7 3-M syndrome, Yakut short stature syndrome AR 26 83
LARP7 Alazami syndrome AR 19 10
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 37 70
OBSL1 3-M syndrome AR 13 33
ORC1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 9 10
ORC4 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 24 6
ORC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 7 6
PCNT Microcephalic osteodysplastic primordial dwarfism AR 49 88
POC1A Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome) AR 4 8
RBBP8 Seckel syndrome, Jawad syndrome AR 6 6
RNU4ATAC Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3 AR 15 24
RTTN Microcephaly, short stature, and polymicrogyria with or without seizures AR 16 16
SRCAP Floating-Harbor syndrome AD 16 43
TRIM37 Mulibrey nanism AR 19 23
XRCC4 Short stature, microcephaly, and endocrine dysfunction AR 9 10

* 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 3-M Syndrome / Primordial Dwarfism Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
BCS1L Chr2:219524871 c.-147A>G NM_004328.4
CEP152 Chr15:49059406 c.2148-17G>A NM_001194998.1 rs751691427
CUL7 Chr6:43010511 c.3897+29G>A NM_001168370.1
RBBP8 Chr18:20581745 c.2287+53T>G NM_002894.2
RTTN Chr18:67727297 c.4748-19T>A NM_173630.3
RTTN Chr18:67815044 c.2309+1093G>A NM_173630.3
TRIM37 Chr17:57106096 c.1949-12A>G NM_015294.3
XRCC4 Chr5:82400728 c.-10-1G>T NM_022406.2 rs869320678

Added and removed genes from the panel

Genes added Genes removed


Test Strengths

The strengths of this test include:
  • CAP and ISO-15189 accredited laboratory
  • 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 publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous 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

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 (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • 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 3-M syndrome / primordial dwarfism panel covers classical genes associated with 3-M syndrome, microcephalic primordial dwarfism disorders (mopd), Seckel syndrome, Meier-Gorlin syndrome (Ear-patella-short stature syndrome), Jawad syndrome and Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome. 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 high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999
Insertions, deletions and indels by sequence analysis
1-10 bps 96.9% (7,563/7,806) >99.9999
11-50 bps 99.13% (2,524/2,546) >99.9999
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 143X
Nucleotides with >20x sequencing coverage (%) 99.86%

Bioinformatics

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 and regulatory 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with <20X sequencing depth if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the 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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call.
Reported heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed 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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.

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