Abstract
Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.
Highlights
Over the past two decades, knowledge concerning the mechanisms that control hair growth and differentiation has been increased through the discovery of a small number of disease genes, among others via generation sequencing technologies [1,2,3,4]
We aimed to search for a novel gene that is causative for Hypotrichosis simplex (HS) with woolly hair (WH) in this family and applied two complementary approaches: i) a classical linkage analysis was performed using genome-wide SNP data from 17 related individuals to identify the chromosomal regions co-segregating with the phenotype and (ii) whole exome-sequencing was performed in the index patient to obtain the full spectrum of low-frequency and rare sequence variants in the protein coding regions of the genome
Genome-wide linkage analysis complemented with exome sequencing revealed heterozygous mutations in the F11 and SORBS2 genes segregating with the phenotype in the examined family
Summary
Over the past two decades, knowledge concerning the mechanisms that control hair growth and differentiation has been increased through the discovery of a small number of disease genes, among others via generation sequencing technologies [1,2,3,4]. HS is inherited in an autosomal-dominant or recessive manner [2], and [3] is characterized by a diffuse loss of hair, which usually begins in early childhood and progresses into adulthood. Both within and between families, the extent of scalp and body hair involvement varies, ranging from partial alopecia to a complete loss of scalp and body hair. Some HS patients present with hair that is tightly curled and low in density.
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