- Is a 75 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of short stature and associated disorders.
Number of genes75
CPT codesSEQ 81479
The Blueprint Genetics Comprehensive Short Stature Syndrome Panel (test code MA2101):
Commonly used ICD-10 code(s) when ordering the Comprehensive Short Stature Syndrome Panel
|Q87.1||Meier-Gorlin syndrome (Ear-patella-short stature syndrome)|
|Q87.1||Short stature and associated syndromes|
|Q87.1||Microcephalic primordial dwarfism disorders (MOPD)|
|Q87.1||Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome|
- 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 developmental delay, but there can be significant clinical overlap among syndromes. In addition to the disorders covered by the sub-panels, this comprehensive panel covers several other diseases associated with short stature, such as growth delay due to insulin-like growth factor I resistance or IGF1 deficiency (mutations in IGF1R and IGF1), hypothyroidism due to deficient transcription factors involved in pituitary development or function (HESX1, LHX3, LHX4, POU1F1 and PROP1), Rubinstein-Taybi syndrome (CREBBP and EP300), Cornelia de Lange syndrome (NIPBL, RAD21, SMC3, HDAC8 and SMC1A) and different forms of disproportionate short stature. Disproportionate short stature can manifest itself as short-limbed dwarfism or short-trunk dwarfism. Achondroplasia (autosomal dominant, mutations is FGFR3) is the most common form of disproportionate growth retardation, its estimated incidence is at about 1/25,000 live births worldwide. Identification of rare monogenic causes of short stature is critical since the genetic diagnosis may alert the clinician to other medical comorbidities for which the patient is at risk. For example, a male patient with 3-M syndrome will need to be monitored for the development of hypogonadism. Based on genetic studies in children with severe short stature of unknown etiology it has been suggested that monogenic causes of short stature are underdiagnosed in the pediatric endocrine clinic. Factors that increase the likelihood for a monogenic cause of short stature are severe GH deficiency, multiple pituitary hormone deficiency, unequivocal GH insensitivity, small for gestational age without catch-up growth, additional congenital anomalies or dysmorphic features, associated intellectual disability, microcephaly and height below −3 SD.
Genes in the Comprehensive Short Stature Syndrome Panel and their clinical significance
|ACTG1*||Deafness, Baraitser-Winter syndrome||AD||27||47|
|ATR||Cutaneous telangiectasia and cancer syndrome, Seckel syndrome||AD/AR||10||33|
|B3GAT3*||Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects||AR||6||13|
|BCS1L||Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1||AR||42||37|
|BRAF*||LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome||AD||134||65|
|CBL||Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia||AD||24||43|
|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|
|CUL7||3-M syndrome, Yakut short stature syndrome||AR||26||83|
|FGD1||Aarskog-Scott syndrome, Mental retardation, syndromic||XL||29||51|
|FGFR3||Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN||AD/AR||54||77|
|GH1*||Isolated growth hormone deficiency, Kowarski syndrome||AD/AR||25||90|
|GHR||Growth hormone insensitivity syndrome (Laron syndrome)||AD/AR||35||115|
|GHRHR||Isolated growth hormone deficiency||AR||13||51|
|GNAS||McCune-Albright syndrome, Progressive osseous heteroplasia, Pseudohypoparathyroidism, Albright hereditary osteodystrophy||AD||64||274|
|HDAC8||Cornelia de Lange syndrome||XL||41||50|
|HESX1||Septooptic dysplasia, Pituitary hormone deficiency, combined||AR/AD||15||26|
|HRAS||Costello syndrome, Congenital myopathy with excess of muscle spindles||AD||43||31|
|IGF1||Insulin-like growth factor I deficiency||AR||4||8|
|IGF1R||Insulin-like growth factor I, resistance||AD/AR||12||64|
|IGFALS||Insulin-like growth factor-binding protein, acid-labile subunit, deficiency||AR||5||34|
|INSR||Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome||AD/AR||44||190|
|IRS1||Diabetes mellitus, noninsulin-dependent||AD/AR||3||17|
|KRAS*||Noonan syndrome, Cardiofaciocutaneous syndrome||AD||63||35|
|LHX3||Pituitary hormone deficiency, combined||AR||9||16|
|LHX4||Pituitary hormone deficiency, combined||AD||10||23|
|LZTR1||Schwannomatosis, Noonan syndrome||AD/AR||34||71|
|NIPBL||Cornelia de Lange syndrome||AD||311||425|
|NOTCH2*||Alagille syndrome, Hajdu-Cheney syndrome||AD||37||70|
|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|
|OTX2||Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction||AD||23||73|
|PCNT||Microcephalic osteodysplastic primordial dwarfism||AR||49||88|
|PITX2||Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly||AD||23||101|
|POC1A||Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome)||AR||4||8|
|POU1F1||Pituitary hormone deficiency, combined||AR||20||41|
|PROP1||Pituitary hormone deficiency, combined||AR||33||37|
|PTPN11||Noonan syndrome, Metachondromatosis||AD||135||140|
|RAD21*||Cornelia de Lange syndrome 4||AD||14||11|
|RAF1||LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM)||AD||45||53|
|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|
|RRAS||Noonan-syndrome like phenotype||AD/AR||2|
|RTTN||Microcephaly, short stature, and polymicrogyria with or without seizures||AR||16||16|
|SHOC2||Noonan-like syndrome with loose anagen hair||AD||2||4|
|SHOX*||Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature||XL/PAR||25||431|
|SMC1A||Cornelia de Lange syndrome||XL||73||87|
|SMC3||Cornelia de Lange syndrome||AD||25||21|
|STAT5B*||Growth hormone insensitivity with immunodeficiency||AR||9||13|
|TBX19||Adrenocorticotropic hormone deficiency||AR||12||27|
|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 Comprehensive Short Stature Syndrome Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- 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
- ~1,500 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
The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: CEP152 (26), RASA2 (3, 6, 17, 19, 20). Genes with suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
- 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 comprehensive short stature syndrome panel covers classical genes associated with 3-M syndrome, Seckel syndrome, Meier-Gorlin syndrome (Ear-patella-short stature syndrome), Jawad syndrome, Short stature and associated syndromes, microcephalic primordial dwarfism disorders (MOPD) 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 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.
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 the following criteria are not Sanger confirmed: the variant quality score is above the internal threshold for a true positive call, and visual check-up of the variant at IGV is in-line with the variant call. 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.
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.