Abstract
Ectodermal dysplasias (EDs) are a large heterogeneous group of inherited disorders exhibiting abnormalities in ectodermally derived appendages such as hair, nails, teeth and sweat glands. EDs associated with reticulated pigmentation phenotype are rare entities for which the genetic basis and pathophysiology are not well characterized. The present study describes a five generation consanguineous Pakistani family segregating an autosomal recessive form of a novel type of ectodermal dysplasia. The affected members present with sparse and woolly hair, severe nail dystrophy and reticulate skin pigmentation. After exclusion of known gene loci related with other skin disorders, genome-wide linkage analysis was performed using Illumina HumanOmniExpress beadchip SNP arrays. We linked this form of ED to human chromosome 18p11.32-p11.31 flanked by the SNPs rs9284390 (0.113Mb) and rs4797100 (3.14 Mb). A maximum two-point LOD score of 3.3 was obtained with several markers along the disease interval. The linkage interval of 3.03 Mb encompassed seventeen functional genes. However, sequence analysis of all these genes did not discover any potentially disease causing-variants. The identification of this novel locus provides additional information regarding the mapping of a rare form of ED. Further research, such as the use of whole-genome sequencing, would be expected to reveal any pathogenic mutation within the disease locus.
Highlights
IntroductionEctodermal dysplasias (EDs) are a large heterogeneous group of congenital disorders characterized by primary developmental defects in ectodermal appendages (hair, nails, teeth, sweat glands) during morphogenesis/development with or without accompanying defects in other tissues, organs and systems
Ectodermal dysplasias (EDs) are a large heterogeneous group of congenital disorders characterized by primary developmental defects in ectodermal appendages during morphogenesis/development with or without accompanying defects in other tissues, organs and systems
We have presented a clinical and molecular analysis of an unreported ED condition observed in a five generation consanguineous family of Pakistani origin
Summary
Ectodermal dysplasias (EDs) are a large heterogeneous group of congenital disorders characterized by primary developmental defects in ectodermal appendages (hair, nails, teeth, sweat glands) during morphogenesis/development with or without accompanying defects in other tissues, organs and systems. More than 200 EDs with different pathological and clinical manifestations have been reported but causative genes have been identified only in few ED phenotypes. Ectodermal Dysplasia of Hair, Nail and Skin Type (HED; MIM 305100) characterized by hypotrichosis, hypo- or anodontia (abnormal or absent teeth) and hypo-or anhidrosis (reduced or absent sweating) with disease-causing mutations in four genes, namely EDA (MIM 300451), EDAR (MIM 604095), EDARADD (MIM 606603) and TRAF6 (MIM 602355). X-linked recessive (EDA), autosomal dominant and recessive (EDAR, EDARADD, TRAF6) inherited HED forms have been reported. Many genetic causes of rare EDs were reported as e.g. mutations in the HOXC13 gene (MIM 142976) [1], a member of the HOX family of transcription factors, causing pure hair and nail ectodermal dysplasia (PHNED; MIM 614931), mutations in the KCTD1 gene (MIM 613420) [2] for scalp-ear-nipple syndrome (SENS; MIM 181270) and recently pathogenic variants in GRHL2 gene causing an autosomal-recessive ectodermal dysplasia syndrome [3]
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