Identification Of A Novel Locus For A New Clinical Variant Of Hereditary Alopecia In A Large Chinese Family By A Genome-Wide Scan

Backgrounds Hereditary alopecia or hypotrichosis is a large and heterogeneous group of inherited hair disorders featuring complete or partial and permanent absence of hairs since birth or childhood. About sixty diseases are included in this group of disorders. These disorders transmit as autosomal dominant, autosomal recessive or X-linked dominant or recessive mode of inheritance. The histopathological examination of biopsy shows the decrease or absence of hair follicles and atrophy of hair bulbs. This condition may occur as an isolated defect, or as a feature of a hereditary syndrome, usually in association with other ectodermal abnormalities. The isolated hair disorders include alopecia universalis congenita or alopecia with papular lesions, hypotrichosis simplex, hypotrichosis simplex of scalp, localized autosomal recessive hypotrichosis, loose anagen syndrome and Marie Unna hereditary hypotrichosis etc. The syndromic hair disorders include hypotrichosis with juvenile macular dystrophy, vitamin D-dependent rickets, hypohidrotic or hidrotic ectodermal dysplasia, Bazex syndrome, T-cell immunodeficiency-congenital alopecia-nail dystrophy, tricho-rhino-palangeal-syndrome, monilethrix, Netherton syndrome, Bjornstad syndrome, Menkes syndrome, trichothiodystrophy, cartilage hair hypoplasia, Rothmund-Thamson syndome etc. The inherited hair disorders are classified into disorders of hair morphogenesis, hair cycling, and hair shaft structure on the basis of pathogenesis. A number of genetic loci or genes responsible for some hereditary alopecia/hypotrichosis have been identified in in recently ten years, such as 8p21, 6p21, 18p11, 16q22, 18q12, 3q26, 1p21 loci, and HR,CDH3,K6HF,CDSN,DSG4,LIPH genes.Objectives (1) to analyze the clinical features of one Chinese family with one rare clinical variant of hereditary alopecia. (2) to map the gene responsible for this type of hereditary alopecia.Methods (1) The family with hereditary localized alopecia is studied by on-the-spot investigation, histopathology, scanning electron microscopy. Then, we collect blood samples from 16 individuals and performe a genome-wide scan with 382 fluorescent microsatellite markers. Linkage software and Cyrillic software are used for linkage and haplotype analyses. Then additional ten microsatellite markers are used for fine mapping. (2) We analyze the function and expression of all known genes in the interval to determine the reasonable candidate genes.Results Thirteen of totally thirty-eight individuals in a four generation Chinese family are affected, including six males and seven females. The mode of inheritance is autosomal dominant transmission. All affected individuals present with partial absence of hairs on the frontal and occipital region of scalp at birth. The appearance of the affected scalp is normal. Moreover, all patients except individual IV6 and IV12 also present with complete absence of eyebrows and eyelashes. However, their axillary, pubic and body hairs are normal. Their teeth, nails, sweat secretion, physical or mental development is also normal. Moreover, affected individuals also have facial freckling. In the proband, individual IV7, numerous small keratinizing follicular papules are diffusely distributed on his trunk, consistent with keratosis pilaris. A punch biopsy from the proband's affected scalp reveal strikingly decreased hair follicles with no significant inflammatory infiltrate. Scanning electron microscopy of hairs plucked from the involved area reveal complete peeling or decrease of cuticles, a longitudinal groove and fracture in the hair shaft, with normal circular appearance. (2) An autosomal dominant inheritance with 99.9% penetrance and a frequency of 0.0001 for the disease allele are assumed. We performe genome-wide scan and find a maximum LOD score from the marker D2S2667 (Zmax=3.84,θ=0.00). Haplotypes analysis suggests the gene responsible for this autosomal dominant hereditary localized alopecia lies in the 28.30 cM interval between marker D2S287 and D2S165.Conclusions (1) Our study strongly suggests that this family may represent a new clinical variant of hereditary alopecia or hypotrichosis that is clinically and genetically distinct from previously described cases. (2) We identify a novel locus of hereditary alopecia on chromosome 2p25.1-2p23.2. It indicates there is genetic heterogeneity among the hereditary alopecia or hypotrichosis.