C. Ni

Genotype-phenotype correlation of xeroderma pigmentosum in a Chinese Han population.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to sunlight, freckle‐like pigmentation and a greatly increased incidence of skin cancers. Genetic mutation detection and genotype–phenotype analysis of XP are rarely reported in the Chinese Han population.

A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome

Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks—mutilating palmoplanter and periorificial keratoderma. However, there’s a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease.

Report of Chinese family with severe dermatitis, multiple allergies and metabolic wasting syndrome caused by novel homozygous desmoglein-1 gene mutation

Recently, homozygous mutations in the desmoglein‐1 (DSG1) gene and heterozygous mutation in the desmoplakin (DSP) gene have been demonstrated to be associated with severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome (Mendelian Inheritance in Man no. 615508). We aim to identify the molecular basis for a Chinese pedigree of SAM syndrome. A Chinese pedigree of SAM syndrome was subjected to mutation detection in the DSG1 gene. Sequence analysis of the DSG1 gene and quantitative reverse transcriptase polymerase chain reaction analysis for gene expression of DSG1 using cDNA derived from the epidermis of patients and controls were both performed. Skin biopsies were also taken from patients for pathological study and transmission electron microscopy observation. Novel homozygous splicing mutation c.1892‐1delG in the exon–intron border of the DSG1 gene has been demonstrated to be associated with SAM syndrome. We report a new family of SAM syndrome of Asian decent and expand the spectrum of mutations in the DSG1 gene.

Genome-wide linkage analysis and whole-genome sequencing identify a recurrent SMARCAD1 variant in a unique Chinese family with Basan syndrome

Basan syndrome is a rare autosomal dominant genodermatosis, characterized by rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. A mutation in the SMARCAD1 gene was recently reported to cause Basan syndrome in one family. Here, we present a large Chinese family with Basan syndrome; some patients presented with hyperpigmentation and knuckle pads in addition to previously reported clinical manifestations. We used genome-wide linkage analysis and whole-genome sequencing (WGS) to identify the pathogenic gene in this unique pedigree. Genome-wide linkage analysis successfully mapped the candidate gene to 4p15.31-4p14 and 4q13.2-4q23. The maximal LOD score was 3.01. WGS in one patient identified a splice variant (c.378+1G>T) in the SMARCAD1 gene (NG_031945.1) that was confirmed by Sanger sequencing. Co-segregation of the variant was confirmed in this pedigree. The same variant was recently found to be associated with isolated adermatoglyphia (ADG) in another family, suggesting that this variant is causative for both Basan syndrome and autosomal dominant ADG (OMIM 136 000). This indicates that ADG and Basan syndrome may be the phenotypic variants of the same disease. Further studies should be performed to elucidate the pathogenic mechanisms induced by this variant. This report increases the phenotypic spectrum of Basan syndrome and furthers our understanding of the genetic basis of this disease. Our results also highlight the power of combining WGS and genome-wide linkage analysis in identifying causative genes in pedigrees with a genetic disorder.

Nagashima-type palmoplantar keratosis in a Chinese Han population.

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive form of palmoplantar keratoderma (PPK), which is caused by mutations in the SERPINB7 gene. NPPK has only been reported in Japanese and Chinese populations. The present study was conducted on 12 unrelated Chinese patients who were clinically predicted to suffer from NPPK. Mutation screening was performed by direct sequencing of the entire coding regions of SERPINB7, SLURP1, AQP5, CSTA, KRT1 and KRT9 genes. Direct sequencing of SERPINB7 revealed five homozygous founder mutations (c.796C>T) and four compound heterozygous mutations in nine patients, including one novel mutation (c.122_127delTGGTCC). Nine out of the 12 patients were diagnosed with NPPK due to SERPINB7 pathogenic mutations, and the results expanded the known mutation spectrum of NPPK. Taking the other seven reported Chinese patients, who had been definitively diagnosed with NPPK by genetic testing, into account, the present study further demonstrated that NPPK is a common entity in Mainland China, and c.796C>T is the most prevalent mutation and exerts a founder effect. Furthermore, the NPPK cases described in the current study presented a consistently mild phenotype, as compared with the degrees of phenotypic variability associated with other types of relatively severe PPK, including Mal de Meleda and Olmsted syndrome.

Novel MBTPS2 missense mutation causes a keratosis follicularis spinulosa decalvans phenotype: mutation update and review of the literature.

Keratosis follicularis spinulosa decalvans (KFSD) is an X‐linked condition characterized by keratotic follicular papules and progressive alopecia, which is caused by mutations in the MBTPS2 gene. We carried out a genetic study on a child who was suspected clinically to have KFSD. Sanger sequencing was performed to detect mutations in the entire coding region of MBTPS2. A novel missense mutation (c.599C>T) was identified in the patient, confirming a diagnosis of KFSD. We reviewed related cases with MBTPS2 mutations for evidence of genotype–phenotype correlations.

Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination

Pathogenic mutations in genes (SASH1 and PTPN11) can cause a rare genetic disorder associated with pigmentation defects and the well‐known LEOPARD syndrome, respectively. Both conditions presented with lentiginous phenotypes. The aim of this study was to arrive at definite diagnoses of three Chinese boys with clinically suspected lentigines‐related syndromes. ADAR1, ABCB6, SASH1 and PTPN11 were candidate genes for mutational screening. Sanger sequencing was performed to identify the mutations, whereas bioinformatic analysis was used to predict the pathogenicity of novel missense mutations. Two novel mutations c.1537A>C (p.Ser513Arg) and 1527_1530dupAAGT (p.Leu511Lysfs*21) in SASH1 and a common p.Thr468Met mutation in PTPN11 were detected in three pediatric patients with lentiginous phenotypes, respectively. Comparisons between clinical presentations showed that SASH1‐related phenotypes can exhibit hyper‐ and hypopigmentation on the trunk and extremities, similar to dyschromatosis, while scattered café au‐lait spots usually appeared in PTPN11‐related LEOPARD syndrome. Furthermore, the similarity in the clinical presentations of Peutz–Jeghers syndrome, Laugier–Hunziker syndrome, xeroderma pigmentosum, neurofibromatosis type I, suggesting that these conditions should be added into the differential diagnoses of lentiginous phenotypes.

Report of a sporadic familial progressive hyper‐ and hypopigmentation child caused by a novel KITLG mutation

DEAR EDITOR, Familial progressive hyperand hypopigmentation (FPHH, OMIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and caf e au lait spots (CALs). It is caused by a mutation in KITLG, encoding the KIT ligand, which is involved in the Ras/mitogen-activated protein kinase (MAPK) pathway. KITLG and its receptor c-Kit, triggering the Ras/MAPK signalling pathway, play critical roles in regulating physiological and pathological cutaneous pigmentation. Differential diagnoses of FPHH include similar pigmentary genodermatoses such as its allelic disorder familial progressive hyperpigmentation (FPH) and other disorders that show strong association with multiple CALs, including neurofibromatosis type 1 (NF1, OMIM 162200) and Legius syndrome (OMIM 611431), which can be distinguished by mutational analysis. Herein we report a young Chinese boy definitively diagnosed with FPHH via identification of a novel de novo c.101C>T (p.Thr34Ile) mutation in KITLG. The boy’s parents were referred to our department in November 2013, reporting progressive hyperpigmentation, multiple lentigines and CAL-like lesions presenting over his whole body soon after birth. The boy had no developmental abnormalities and dysmorphic craniofacial features. Dermatological examination showed diffuse hyperpigmentation intermixed with lentigines/CAL-like lesions, as well as hypopigmented macules and spots spread out on the entire body (Fig. 1a,b). Notably, freckle-like lesions/lentigines were also present in the axilla (Fig. 1c). No relevant pigmentary abnormalities were observed in his parents (Fig. S1; see Supporting Information), and there were no known consanguineous marriages or family history. Three genes, NF1 (tested as previously reported), SPRED1 and KITLG, were sequenced sequentially. Mutation screening of NF1 and SPRED1 did not reveal any pathogenic mutations. However, a novel heterozygous missense mutation c.101C>T (p.Thr34Ile) in KITLG was identified in the patient. Moreover, this mutation was absent in his unaffected parents and 100 healthy controls (Fig. S2; see Supporting Information). Online in silico programs were applied to predict the potential impact of an amino acid substitution on the structure and function of the KITLG protein. The mutation p.Thr34Ile was predicted to be ‘probably damaging’, ‘deleterious’ and ‘disease causing’ with Polyphen-2 (http://genetics.bwh.harvard.edu/ pph2/), SIFT (http://sift.jcvi.org/) and Mutation Taster (http://www.mutationtaster.org/), respectively. Furthermore, we performed analysis using an online sever, SWISS-MODEL (http://swissmodel.expasy.org/), to construct the three-dimensional structure of KITLG. Next, PyMOL (Schr€ odinger, version 1.3; https://www.pymol.org/) was used to display the protein structure with the mutated amino acid residue (Fig. S3; see Supporting Information). The substitution Ile34 was predicted to affect the binding strength between 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (http://www.rcsb.org/pdb/ligand/ligandsummary.do?hetId= TRS&sid=1EXZ) and KITLG. Two skin specimens – a lentigo/CAL-like lesion (Fig. 2c) and a hyperpigmented macule with a small hypopigmented lesion (Fig. 2a) – were collected from the arm and the thigh of the patient, respectively. Firstly, tissue sections of these two skin specimens were histologically examined by conventional haematoxylin and eosin staining (Fig. 2; Fig. S4; see Supporting Information). Next, skin tissue sections of the patient were investigated by immunohistochemical staining (skin specimens

Genome-wide linkage and exome sequencing analyses identify an initiation codon mutation of KRT5 in a unique Chinese family with generalized Dowling–Degos disease

DEAR EDITOR, Dowling–Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by reticulate pigmentation of the flexures in combination with an irregular elongation of thin branching rete ridges in histopathology. A special form called generalized DDD has also been reported, which presents predominantly with hyperand/or hypopigmented macules on the neck, chest and abdomen instead of reticulate hyperpigmentation confined to the flexor areas. Loss-of-function mutations in KRT5, POFUT1, POGLUT1 and one candidate gene mapping at 17q21.3–q22 have been identified as being responsible for classical DDD or generalized DDD.

Mutations in the mevalonate pathway genes in Chinese patients with porokeratosis

Porokeratosis (PK, MIM 175800) is a chronic autosomal dominant cutaneous keratinization disorder, which has a wide variety of clinical manifestations.