Comprehensive Short Stature Syndrome Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: MA2101

The Blueprint Genetics Comprehensive Short Stature Syndrome Panel is a 61 gene test for genetic diagnostics of patients with clinical suspicion of short stature and associated syndromes.

Numerous monogenic causes of growth disorders have been identified. This panel covers several disorders associated with short stature with autosomal recessive and dominant modes of inheritance. This comprehensive Panel includes (but is not limited to) disorders covered by the subpanels: 3-M Syndrome / Primordial Dwarfism Panel, Meier-Gorlin Syndrome Panel and Seckel Syndrome Panel. This Panel is part of the Comprehensive Skeletal / Malformation Syndrome Panel.

About Short Stature Syndromes

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) 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, evidence of a skeletal dysplasia, associated intellectual disability, microcephaly and height below −3 SD.


Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more:

Genes in the Comprehensive Short Stature Syndrome Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
AKT1 Proteus syndrome, Cowden syndrome AD 5 6
ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 8 18
BMP2 Brachydactyly type A2 AD 1 19
BMP4 Microphthalmia, syndromic, Orofacial cleft AD 9 34
BMPR1A* Polyposis, juvenile intestinal AD 65 119
CDC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 2
CDT1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 6 10
CENPJ Seckel syndrome, Microcephaly AR 28 7
CEP63 Seckel syndrome AR 5 2
CEP152 Seckel syndrome, Microcephaly AR 15 18
CREBBP Rubinstein-Taybi syndrome AD 138 340
CUL7 3-M syndrome, Yakut short stature syndrome AR 21 74
DHCR7 Smith-Lemli-Opitz syndrome AR 64 214
EP300 Rubinstein-Taybi syndrome AD 43 81
EYA1 Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome AD 39 197
FGD1 Aarskog-Scott syndrome, Mental retardation, syndromic XL 21 47
FGF3 Deafness, congenital with inner ear agenesis, microtia, and microdontia AR 13 20
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 53 70
FOXL2 Premature ovarian failure, Blepharophimosis, epicanthus inversus, and ptosis AD 71 209
GH1* Isolated growth hormone deficiency, Kowarski syndrome AD/AR 24 86
GHR Growth hormone insensitivity syndrome (Laron syndrome) AD/AR 33 100
GHRHR Isolated growth hormone deficiency AR 14 43
GLI2 Culler-Jones syndrome AD 21 76
HESX1 Septooptic dysplasia, Pituitary hormone deficiency, combined AR/AD 11 26
IGF1 Insulin-like growth factor I deficiency AR 4 8
IGF1R Insulin-like growth factor I, resistance AD/AR 9 58
IGFALS Insulin-like growth factor-binding protein, acid-labile subunit, deficiency AR 5 31
INSR Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome AD/AR 40 175
IRS1 Diabetes mellitus, noninsulin-dependent AD/AR 2 14
KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 59 31
LHX3 Pituitary hormone deficiency, combined AR 9 16
LHX4 Pituitary hormone deficiency, combined AD 9 23
NIPBL Cornelia de Lange syndrome AD 268 417
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 25 61
NR5A1 Adrenocortical insufficiency, Premature ovarian failure, 46,XY sex reversal AD/AR 26 165
OBSL1 3-M syndrome AR 12 29
ORC1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 9 9
ORC4 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 22 5
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 17 65
PCNT Microcephalic osteodysplastic primordial dwarfism AR 42 83
PITX2 Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly AD 19 95
POU1F1 Pituitary hormone deficiency, combined AR 20 41
PROP1 Pituitary hormone deficiency, combined AR 27 34
PTCH1 Basal cell nevus syndrome AD 122 397
PTPN11 LEOPARD syndrome, Noonan syndrome, Metachondromatosis AD 124 135
RAF1 LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM) AD 44 43
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 21
SHH Holoprosencephaly, Microphthalmia with coloboma AD 35 216
SHOX* Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature XL/PAR 24 424
SIX3 Holoprosencephaly AD 12 83
SMC1A Cornelia de Lange syndrome XL 50 84
SOS1 Noonan syndrome AD 45 66
SOX2* Microphthalmia, syndromic AD 25 99
SOX3 Panhypopituitarism XL 4 25
STAT5B* Growth hormone insensitivity with immunodeficiency AR 5 10
TBX3 Ulnar-Mammary syndrome AD 6 20
TBX19 Adrenocorticotropic hormone deficiency AR 5 27
TGIF1 Holoprosencephaly AD 7 25
ZIC2 Holoprosencephaly AD 16 112

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (; HGMD, refers to a 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 CDG ( or Orphanet ( databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
GH1 Chr17:61995349 c.291+28G>A NM_000515.3 rs863223306
RBBP8 Chr18:20581745 c.2287+53T>G NM_002894.2
SHOX ChrX:585124 c.-645_-644insGTT NM_000451.3

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist


This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.


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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)


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.

Blueprint Genetics offers a Comprehensive Short Stature Syndrome Panel that covers classical genes associated with 3-M syndrome, Jawad syndrome, meier-Gorlin syndrome (Ear-patella-short stature syndrome), microcephalic primordial dwarfism disorders (MOPD), Seckel syndrome, short stature and associated syndromes and short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (, the NHLBI GO Exome Sequencing Project (ESP;, the Exome Aggregation Consortium (ExAC;, ClinVar database of genotype-phenotype associations ( and the Human Gene Mutation Database ( The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (, Polyphen (, and Mutation Taster (

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479

ICD codes

Commonly used ICD-10 codes when ordering the Comprehensive Short Stature Syndrome Panel

ICD-10 Disease
Q87.1 Short stature and associated syndromes

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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