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 Nurnberg, Johannes Zschocke, Guntram Borck, Matthias Schmuth, Adnan S. Alabdulkareem, Kholood Abdulaziz Alnutaifi, Hans Christian Hennies

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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.
Original languageEnglish
Pages (from-to)e539
JournalMolecular genetics & genomic medicine
Volume7
Issue number3
Early online date1 Jan 2019
DOIs
Publication statusPublished - 1 Mar 2019

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

Keywords

  • ATP-Binding Cassette Transporters/genetics
  • Adolescent
  • Child
  • Cytochrome P-450 Enzyme System/genetics
  • Female
  • Genes, Recessive
  • Genotype
  • Humans
  • Ichthyosiform Erythroderma, Congenital/epidemiology
  • Lipoxygenase/genetics
  • Male
  • Mutation Rate
  • Pakistan
  • Phenotype
  • Receptors, Cell Surface/genetics
  • Saudi Arabia
  • Transglutaminases/genetics
  • Young Adult

Cite this

Cunha, Dulce Lima ; Alakloby, Omar Mohammed ; Gruber, Robert ; Kakar, Naseebullah ; Ahmad, Jamil ; Alawbathani, Salem ; Plank, Roswitha ; Eckl, Katja ; Krabichler, Birgit ; Altmüller, Janine ; Nurnberg, Peter ; Zschocke, Johannes ; Borck, Guntram ; Schmuth, Matthias ; Alabdulkareem, Adnan S. ; Alnutaifi, Kholood Abdulaziz ; Hennies, Hans Christian. / 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.
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Cunha, DL, Alakloby, OM, Gruber, R, Kakar, N, Ahmad, J, Alawbathani, S, Plank, R, Eckl, K, Krabichler, B, Altmüller, J, Nurnberg, P, Zschocke, J, Borck, G, Schmuth, M, Alabdulkareem, AS, Alnutaifi, KA & 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, 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. / Cunha, Dulce Lima; Alakloby, Omar Mohammed; Gruber, Robert; Kakar, Naseebullah; Ahmad, Jamil; Alawbathani, Salem; Plank, Roswitha; Eckl, Katja; Krabichler, Birgit; Altmüller, Janine; Nurnberg, Peter; Zschocke, Johannes; Borck, Guntram; Schmuth, Matthias; Alabdulkareem, Adnan S.; Alnutaifi, Kholood Abdulaziz; Hennies, Hans Christian.

In: Molecular genetics & genomic medicine, Vol. 7, No. 3, 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 - Cunha, Dulce Lima

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 - Nurnberg, Peter

AU - Zschocke, Johannes

AU - Borck, Guntram

AU - Schmuth, Matthias

AU - Alabdulkareem, Adnan S.

AU - Alnutaifi, Kholood Abdulaziz

AU - Hennies, Hans Christian

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.

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KW - Adolescent

KW - Child

KW - Cytochrome P-450 Enzyme System/genetics

KW - Female

KW - Genes, Recessive

KW - Genotype

KW - Humans

KW - Ichthyosiform Erythroderma, Congenital/epidemiology

KW - Lipoxygenase/genetics

KW - Male

KW - Mutation Rate

KW - Pakistan

KW - Phenotype

KW - Receptors, Cell Surface/genetics

KW - Saudi Arabia

KW - Transglutaminases/genetics

KW - Young Adult

UR - http://www.mendeley.com/research/unknown-mutations-genotypephenotype-correlations-autosomal-recessive-congenital-ichthyosis-patients

U2 - https://doi.org/10.1002/mgg3.539

DO - https://doi.org/10.1002/mgg3.539

M3 - Article

C2 - 30600594

VL - 7

SP - e539

JO - Molecular genetics & genomic medicine

JF - Molecular genetics & genomic medicine

SN - 2324-9269

IS - 3

ER -