Congenital generalized lipodystrophy: Identification of novel variants and expansion of clinical spectrum

A. Haghighi, Z. Kavehmanesh, A. Haghighi, F. Salehzadeh, F. Santos-Simarro, L. Van Maldergem, L. Cimbalistiene, F. Collins, M. Chopra, S. Al-Sinani, S. Dastmalchian, D. C. de Silva, H. Bakhti, A. Garg, P. Hilbert

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.

Original languageEnglish (US)
JournalClinical Genetics
DOIs
StateAccepted/In press - 2015

Fingerprint

Congenital Generalized Lipodystrophy
Hypertrophy
Hypertrichosis
Steatorrhea
Bone Cysts
Umbilical Hernia
Nephrolithiasis
Hepatomegaly
Genetic Counseling
Genetic Association Studies
Adipose Tissue
Anemia
Seizures
Breast

Keywords

  • AGPAT2
  • BSCL2
  • CGL1
  • CGL2
  • Congenital generalized lipodystrophy
  • Genotype-phenotype correlations
  • Novel variants

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Haghighi, A., Kavehmanesh, Z., Haghighi, A., Salehzadeh, F., Santos-Simarro, F., Van Maldergem, L., ... Hilbert, P. (Accepted/In press). Congenital generalized lipodystrophy: Identification of novel variants and expansion of clinical spectrum. Clinical Genetics. https://doi.org/10.1111/cge.12623

Congenital generalized lipodystrophy : Identification of novel variants and expansion of clinical spectrum. / Haghighi, A.; Kavehmanesh, Z.; Haghighi, A.; Salehzadeh, F.; Santos-Simarro, F.; Van Maldergem, L.; Cimbalistiene, L.; Collins, F.; Chopra, M.; Al-Sinani, S.; Dastmalchian, S.; de Silva, D. C.; Bakhti, H.; Garg, A.; Hilbert, P.

In: Clinical Genetics, 2015.

Research output: Contribution to journalArticle

Haghighi, A, Kavehmanesh, Z, Haghighi, A, Salehzadeh, F, Santos-Simarro, F, Van Maldergem, L, Cimbalistiene, L, Collins, F, Chopra, M, Al-Sinani, S, Dastmalchian, S, de Silva, DC, Bakhti, H, Garg, A & Hilbert, P 2015, 'Congenital generalized lipodystrophy: Identification of novel variants and expansion of clinical spectrum', Clinical Genetics. https://doi.org/10.1111/cge.12623
Haghighi A, Kavehmanesh Z, Haghighi A, Salehzadeh F, Santos-Simarro F, Van Maldergem L et al. Congenital generalized lipodystrophy: Identification of novel variants and expansion of clinical spectrum. Clinical Genetics. 2015. https://doi.org/10.1111/cge.12623
Haghighi, A. ; Kavehmanesh, Z. ; Haghighi, A. ; Salehzadeh, F. ; Santos-Simarro, F. ; Van Maldergem, L. ; Cimbalistiene, L. ; Collins, F. ; Chopra, M. ; Al-Sinani, S. ; Dastmalchian, S. ; de Silva, D. C. ; Bakhti, H. ; Garg, A. ; Hilbert, P. / Congenital generalized lipodystrophy : Identification of novel variants and expansion of clinical spectrum. In: Clinical Genetics. 2015.
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abstract = "Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.",
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AU - Haghighi, A.

AU - Salehzadeh, F.

AU - Santos-Simarro, F.

AU - Van Maldergem, L.

AU - Cimbalistiene, L.

AU - Collins, F.

AU - Chopra, M.

AU - Al-Sinani, S.

AU - Dastmalchian, S.

AU - de Silva, D. C.

AU - Bakhti, H.

AU - Garg, A.

AU - Hilbert, P.

PY - 2015

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N2 - Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.

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