Exome Sequencing Search Causal Gene For Autosomal Dominant Hereditary Hypotrichosis Simplex

Background Hereditary hypotrichosis （HH） is a heterogeneous group of inherited hair loss disorders with variant clinical features, modes of inheritance, and genetic bases. Hair loss is diffuse and usually begins in early childhood, and then progresses until adulthood. Hereditary hypotrichosis simplex （HHS） is a form of nonsyndromic inherited hair loss disorders without characteristic hair shaft changes, which has marked genetic and clinical heterogeneity. HHS is known to be inherited as either an autosomal dominant （ADHHS） or autosomal recessive （ARHHS） trait. ADHHS comprises three forms （HHS1、HHS2、HHS3） which are caused by mutations in APCDD1、RPL21、 SNRPE gene, respectively, however, its pathogenesis has not been clearly elucidated. Objective We plan to identify the causative gene in a family with autosomal dominant hereditary hypotrichosis simplex to provide some basis for further gene diagnosis and genetic counseling.Methods （1） Exome sequencing was conducted in two affected individuals and two unaffected individuals from this ADHHS family.（2）We got some candidate genes by genetic analysis.（3）We sequenced mutations of the candidate genes in8affected individuals and8unaffected individuals in this family to identify complete co-segregation between the mutation and ADHHS phenotype.Results （1）119variants were eventually considered as candidate variants. However, the only candidate variant of LPIN1（NM₁45693:exonl2:c.1645A>G:p.K549E） in the2p25.1-2p23.2region had been excluded after we validated for the mutation by Sanger sequencing.（2） We targeted other possible genes （RPL21, APCDD1, SNRPE） and screened candidate variants. Unexpectedly, only a heterozygous missense mutation （NM₀00982:exon3:c.95G>A:p.R32Q） in RPL21remained. We performed PCR amplification and direct sequencing of exon12in RLP21among16individuals. The result revealed that this mutation occurred in all eight affected individuals and the proband’s25-year-old sister with normal phenotype, but not in other unaffected individuals and200healthy controls.（3） An affected individuals died in dysphagia, another two affected individuals were dignosed as esophagus cancer.Conclusion （1） A heterozygous missense mutation （NM₀00982:exon3:c.95G>A: p.R32Q） in RPL21is involved in the genetic pathogenesis of this ADHHS family.（2） An unaffected individual with normal phenotype is likely to be a phenomenon of incomplete penetrance of RPL21.（3） The mutation of RPL21may also be associated with the pathogenesis of esophagus cancer beside alopecia in this family.