A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature

M. Crippa, S. Giangiobbe, R. Villa, I. Bestetti, T. De Filippis, L. Fatti, J. Taurino, L. Larizza, L. Persani, F. Bellini, P. Finelli, M. T. Bonati

Research output: Contribution to journalArticle

Abstract

Purpose: Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24). Methods: FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA. Result: The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression. Conclusions: This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.

Original languageEnglish
Pages (from-to)929-936
Number of pages8
JournalJournal of Endocrinological Investigation
Volume41
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

Fingerprint

Phenotype
Genes
Growth
Osteochondritis Dissecans
Haploinsufficiency
Bone and Bones
Gene Amplification
Age of Onset
Osteoarthritis
Introns
Real-Time Polymerase Chain Reaction
Complementary DNA
Chromosomes
Mothers
Polymerase Chain Reaction
Therapeutics
Intervertebral disc disease

Keywords

  • Aggrecanopathies
  • Bone age advancement
  • Chromosome translocation
  • Decreased growth spurt
  • Proportionate short stature

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

@article{aea93eaccfa7412fb3cdef1cfb5d0e3a,
title = "A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature",
abstract = "Purpose: Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24). Methods: FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA. Result: The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression. Conclusions: This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.",
keywords = "Aggrecanopathies, Bone age advancement, Chromosome translocation, Decreased growth spurt, Proportionate short stature",
author = "M. Crippa and S. Giangiobbe and R. Villa and I. Bestetti and {De Filippis}, T. and L. Fatti and J. Taurino and L. Larizza and L. Persani and F. Bellini and P. Finelli and Bonati, {M. T.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1007/s40618-017-0819-3",
language = "English",
volume = "41",
pages = "929--936",
journal = "Journal of Endocrinological Investigation",
issn = "0391-4097",
publisher = "Springer International Publishing",
number = "8",

}

TY - JOUR

T1 - A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature

AU - Crippa, M.

AU - Giangiobbe, S.

AU - Villa, R.

AU - Bestetti, I.

AU - De Filippis, T.

AU - Fatti, L.

AU - Taurino, J.

AU - Larizza, L.

AU - Persani, L.

AU - Bellini, F.

AU - Finelli, P.

AU - Bonati, M. T.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Purpose: Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24). Methods: FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA. Result: The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression. Conclusions: This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.

AB - Purpose: Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24). Methods: FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA. Result: The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression. Conclusions: This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.

KW - Aggrecanopathies

KW - Bone age advancement

KW - Chromosome translocation

KW - Decreased growth spurt

KW - Proportionate short stature

UR - http://www.scopus.com/inward/record.url?scp=85040034782&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040034782&partnerID=8YFLogxK

U2 - 10.1007/s40618-017-0819-3

DO - 10.1007/s40618-017-0819-3

M3 - Article

C2 - 29302920

AN - SCOPUS:85040034782

VL - 41

SP - 929

EP - 936

JO - Journal of Endocrinological Investigation

JF - Journal of Endocrinological Investigation

SN - 0391-4097

IS - 8

ER -