Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan

Dulce Lima Cunha, Omar Mohammed Alakloby, Robert Gruber, Naseebullah Kakar, Jamil Ahmad, Salem Alawbathani, Roswitha Plank, Katja Eckl, Birgit Krabichler, Janine Altmüller, Peter Nürnberg, Johannes Zschocke, Guntram Borck, Matthias Schmuth, Adnan S. Alabdulkareem, Kholood Abdulaziz Alnutaifi, H. C. Hennies

Research output: Contribution to journalArticle

Abstract

Background: Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods: Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results: We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion: Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI.

LanguageEnglish
Article numbere539
Pagese539
Number of pages12
JournalMolecular genetics & genomic medicine
Volume7
Issue number3
Early online date1 Jan 2019
DOIs
Publication statusPublished - 1 Mar 2019

Fingerprint

Ichthyosis
Saudi Arabia
Pakistan
Genetic Association Studies
Mutation
Lamellar Ichthyosis
Yemen
Skin Diseases
Genes
Permeability
Parents
Skin
Therapeutics

Cite this

Lima Cunha, Dulce ; Alakloby, Omar Mohammed ; Gruber, Robert ; Kakar, Naseebullah ; Ahmad, Jamil ; Alawbathani, Salem ; Plank, Roswitha ; Eckl, Katja ; Krabichler, Birgit ; Altmüller, Janine ; Nürnberg, Peter ; Zschocke, Johannes ; Borck, Guntram ; Schmuth, Matthias ; Alabdulkareem, Adnan S. ; Abdulaziz Alnutaifi, Kholood ; Hennies, H. C. / Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan. In: Molecular genetics & genomic medicine. 2019 ; Vol. 7, No. 3. pp. e539.
@article{28a34c4909a744bb94930a3b7da5f210,
title = "Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan",
abstract = "Background: Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods: Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results: We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion: Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI.",
keywords = "congenital ichthyosis, erythema, genotype/phenotype correlation, homozygosity mapping, Skin permeability barrier, skin scaling",
author = "{Lima Cunha}, Dulce and Alakloby, {Omar Mohammed} and Robert Gruber and Naseebullah Kakar and Jamil Ahmad and Salem Alawbathani and Roswitha Plank and Katja Eckl and Birgit Krabichler and Janine Altm{\"u}ller and Peter N{\"u}rnberg and Johannes Zschocke and Guntram Borck and Matthias Schmuth and Alabdulkareem, {Adnan S.} and {Abdulaziz Alnutaifi}, Kholood and Hennies, {H. C.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1002/mgg3.539",
language = "English",
volume = "7",
pages = "e539",
journal = "Molecular genetics & genomic medicine",
issn = "2324-9269",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

Lima Cunha, D, Alakloby, OM, Gruber, R, Kakar, N, Ahmad, J, Alawbathani, S, Plank, R, Eckl, K, Krabichler, B, Altmüller, J, Nürnberg, P, Zschocke, J, Borck, G, Schmuth, M, Alabdulkareem, AS, Abdulaziz Alnutaifi, K & Hennies, HC 2019, 'Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan', Molecular genetics & genomic medicine, vol. 7, no. 3, e539, pp. e539. https://doi.org/10.1002/mgg3.539

Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan. / Lima Cunha, Dulce; Alakloby, Omar Mohammed; Gruber, Robert; Kakar, Naseebullah; Ahmad, Jamil; Alawbathani, Salem; Plank, Roswitha; Eckl, Katja; Krabichler, Birgit; Altmüller, Janine; Nürnberg, Peter; Zschocke, Johannes; Borck, Guntram; Schmuth, Matthias; Alabdulkareem, Adnan S.; Abdulaziz Alnutaifi, Kholood; Hennies, H. C.

In: Molecular genetics & genomic medicine, Vol. 7, No. 3, e539, 01.03.2019, p. e539.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan

AU - Lima Cunha, Dulce

AU - Alakloby, Omar Mohammed

AU - Gruber, Robert

AU - Kakar, Naseebullah

AU - Ahmad, Jamil

AU - Alawbathani, Salem

AU - Plank, Roswitha

AU - Eckl, Katja

AU - Krabichler, Birgit

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Zschocke, Johannes

AU - Borck, Guntram

AU - Schmuth, Matthias

AU - Alabdulkareem, Adnan S.

AU - Abdulaziz Alnutaifi, Kholood

AU - Hennies, H. C.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background: Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods: Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results: We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion: Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI.

AB - Background: Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods: Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results: We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion: Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI.

KW - congenital ichthyosis

KW - erythema

KW - genotype/phenotype correlation

KW - homozygosity mapping

KW - Skin permeability barrier

KW - skin scaling

UR - http://www.scopus.com/inward/record.url?scp=85062972825&partnerID=8YFLogxK

U2 - 10.1002/mgg3.539

DO - 10.1002/mgg3.539

M3 - Article

VL - 7

SP - e539

JO - Molecular genetics & genomic medicine

T2 - Molecular genetics & genomic medicine

JF - Molecular genetics & genomic medicine

SN - 2324-9269

IS - 3

M1 - e539

ER -