- We have updated the previously published algorithm for the genetic evaluation of short stature1.(Fig. 1) with the following alterations:
- Girls who show persistent or evolving short stature in childhood should have a karyotype included in their initial short stature/failure-to-thrive work-up as screening for Turner syndrome, which is often delayed until adolescence,2.resulting in missed opportunities for condition-specific interventions. A referral to endocrinology should be considered in early childhood, because a sex bias in short stature referrals has been found.
- Chromosomal microarray (comparative genomic hybridization [CGH] and/or single-nucleotide polymorphism [SNP]) should be part of the initial genetic work-up for idiopathic short stature (ISS) and small for gestational age (SGA) with persistent short stature as well as syndromic short stature, since the yield of pathogenic and likely pathogenic copy-number variants (CNV) was reported as high as 10% in this population in one study.4.Multiple studies have reaffirmed use of microarray as first-line testing in patients with syndromic short stature with an average yield of 10–15%.
Copy number variants in patients with short stature.Eur. J. Hum. Genet. 2014; 22: 602-6095.,6.,7.,8.It is important to note that SNP-based chromosomal microarray can document uniparental isodisomy, but not uniparental heterodisomy or methylation patterns.9.,
- Van Duyvendoore H.A.
- et al.
Overview of DNA microarrays: types, applications, and their future.Curr. Protoc. Mol. Biol. 2013; 22: Unit-22.1
- Bumgarner R.
- Rapid technological development has led to the discovery of an increasing number of novel genetic causes for short stature. Multiple genes that cause skeletal dysplasia have been implicated in cases of ISS and SGA with persistent short stature. Several genes associated with endocrinopathies, such as the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis syndromes, have also been observed in children with ISS.11.,12.,13.,14.,15.,16.,17.,18.,19.,20.,21.Therefore, clinical phenotypes of short stature-associated syndromes are expected to expand, and molecular testing for children with short stature should be considered (particularly SHOX) even without overt signs of skeletal dysplasia or endocrinopathy.22.,
- Clinicians should explore the yield and other limitations of individual next-generation sequencing (NGS) panels and array technologies based on the data from the laboratory offering the testing. Clinicians should be aware of difficult-to-sequence regions, including genes located in highly homologous and repetitive regions.
- Further testing with clinical exome sequencing and referral to medical genetics should be considered for patients with the following features suggestive of a monogenic cause for short stature: significant short stature (height < -3 SD), facial dysmorphism, skeletal abnormalities, intellectual disability, microcephaly, multiple pituitary hormone deficiency, severe growth hormone deficiency, SGA with persistent short stature, family history of consanguinity, or family history of one parent with height < -2 SD.25.,26.,27.,28.Current studies assessing diagnostic yield of exome sequencing for syndromic short stature with prior negative karyotype, microarray and NGS targeted panels is reported between 16.5% and 46%.29.,30.,31.,32.Clinical genome sequencing has begun to be offered in select laboratories and can be considered if available. At this time, important considerations include the cost of this testing, insurance reimbursement, and lack of evidence that clinical genome sequencing has a significantly increased diagnostic yield compared with clinical exome sequencing.
- Important resources for clinicians to utilize in the evaluation and management of patients with a genetic diagnosis that includes short stature include disease-specific growth charts (which can be found on CDC.gov or disease-specific organization websites), GeneReviews® and the ACMG and American Academy of Pediatrics (AAP) practice guidelines.
- Because the ACMG 2009 short stature document
- ACMG practice guideline: genetic evaluation of short stature.Genet. Med. 2009; 11: 465-470
- Medically underserved girls receive less evaluation for short stature.Pediatrics. 2011; 127: 696-702
- Sex differences in patients referred for evaluation of poor growth.J. Pediatr. 2005; 146: 212-216
- Copy number variants in patients with short stature.Eur. J. Hum. Genet. 2014; 22: 602-609
- Rare copy number variants are a common cause of short stature.PLoS Genet. 2013; 9: e1003365
- Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways.Eur. J. Endocrinol. 2014; 171: 253-262
- Copy number variants in short children born small for gestational age.Horm. Res. Paediatr. 2014; 82: 310-318
- Recurrent copy number variants associated with syndromic short stature of unknown cause.Horm. Res. Paediatr. 2018; 89: 13-21
- Overview of DNA microarrays: types, applications, and their future.Curr. Protoc. Mol. Biol. 2013; 22: Unit-22.1
- Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG).Genet. Med. 2020; 22: 1133-1141
- Genetic causes of isolated short stature.Arch. Endocrinol. Metab. 2019; 63: 70-78
- Genetic evaluation of short stature.Best Pract. Res. Clin. Endocrinol. Metab. 2011; 25: 1-17
- Large-scaled pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature.J. Clin. Endocrinol. Metab. 2013; 98: E1428-E1437
- Genetic techniques in the evaluation of short stature.Endocrinol. Metab. Clin. North Am. 2016; 45: 345-358
- Mechanisms in endocrinology: novel genetic causes of short stature.Eur. J. Endocrinol. 2016; 174: R145-R173
- Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.Endocr. J. 2017; 64: 947-954
- A genetic approach to evaluation of short stature of undetermined cause.Lancet Diabetes Endocrinol. 2018; 6: 564-574
- Children born small for gestational age: differential diagnosis, molecular genetic evaluations, and clinical implications.Endocr. Rev. 2018; 39: 851-894
- New developments in the genetic diagnosis of short stature.Curr. Opin. Pediatr. 2018; 30: 541-547
- Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel.BMC Med. Genet. 2018; 19
- Multigene sequencing analysis of children born small for gestational age with isolated short stature.J. Clin. Endocrinol. Metab. 2019; 104: 2023-2030
- A track record on SHOX: from basic research to complex models and therapy.Endocr. Rev. 2016; 37: 417-448
- Evaluation of SHOX defects in the era of next-generation sequencing.Clin. Genet. 2019; 96: 261-265
- Limitations of next-generation genome sequence assembly.Nat. Methods. 2011; 8: 61-65
- Towards identification of molecular mechanisms of short stature.Int. J. Pediatr. Endocrinol. 2013; 2013: 19
- Genetic evaluation of short stature.J. Clin. Endocrinol. Metab. 2014; 99: 3080-3092
- Whole exome sequencing to identify genetic causes of short stature.Horm. Res. Paediatr. 2014; 82: 44-52
- Challenges in the management of short stature.Horm. Res. Paediatr. 2016; 85: 2-10
- High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing.Clin Genet. 2017; 92: 594-605
- Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature.Genet. Med. 2018; 20: 630-638
- Genetic evaluation of 114 Chinese short stature children in the next generation era: a single center study.Cell. Physiol. Biochem. 2018; 49: 295-305
- Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing.J. Pediatr. 2019; 215: 192-198
- Clinical genome sequencing in an unbiased pediatric cohort.Genet. Med. 2019; 21: 303-310
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