Xuefu Li

A novel mutation in TNNT3 associated with Sheldon–Hall syndrome in a Chinese family with vertical talus

Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the limb joints. Recently, mutations in genes encoding the fast-twitch skeletal muscle contractile myofibers complex, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosine 2 (TPM2), and embryonic myosin heavy chain 3 (MYH3), and the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1) were confirmed to cause DA1, DA2A, and DA2B. DA2B, or Sheldon-Hall syndrome (SHS; MIM 601680), is intermediate to DA1 and DA2A, or Freeman-Sheldon syndrome (FSS; MIM193700), and shows prominent facial traits. This report describes a Chinese family with SHS over three generations in which all affected individuals showed vertical talus and one demonstrated preauricular tags on the face. Linkage analysis and PCR sequencing revealed a novel substitute mutation at a hot-spot site in TNNT3 (c.187C > T; p.R63C). This mutation was confirmed to cosegregate with the DA phenotype in affected individuals. SIFT and PolyPhen analyses suggest that the mutation is pathogenic. We report this mutation in TNNT3 and speculate that bilateral vertical talus, or severe clubfoot, might be a special characteristic for cases with the TNNT3 R63C mutation.

TGFA and IRF6 Contribute to the Risk of Nonsyndromic Cleft Lip with or without Cleft Palate in Northeast China

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) are common birth defects with a complex etiology. Multiple interacting loci and possible environmental factors influence the risk of NSCL/P. 12 single nucleotide polymorphisms (SNPs) in 7 candidate genes were tested using an allele-specific primer extension for case-control and case-parent analyses in northeast China in 236 unrelated patients, 185 mothers and 154 fathers, including 128 complete trios, and 400 control individuals. TGFA and IRF6 genes showed a significant association with NSCL/P. In IRF6, statistical evidence of an association between rs2235371 (p = 0.003), rs2013162 (p<0.0001) and NSCL/P was observed in case-control analyses. Family based association tests (FBATs) showed over-transmission of the C allele at the rs2235371 polymorphism (p = 0.007). In TGFA, associations between rs3771494, rs3771523 (G3822A), rs11466285 (T3851C) and NSCL/P were observed in case-control and FBAT analyses. Associations between other genes (BCL3, TGFB3, MTHFR, PVRL1 and SUMO1) and NSCL/P were not detected.

A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures.

Distal arthrogryposes (DAs), a clinically and genetically heterogeneous group of disorders characterized by congenital contractures with predominant involvement of the hands and feet, can be classified into at least 12 different forms. These autosomal dominant disorders are of variable expressivity and reduced penetrance. Mutations in sarcomeric protein genes, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosin 2 (TPM2), embryonic myosin heavy chain 3 (MYH3), and myosin binding protein C1 (MYBPC1), have been identified in distal arthrogryposis type 1 (DA1, MIM 108120), type 2B (DA2B, MIM 601680) and type 2A (DA2A)/Freeman-Sheldon syndrome (FSS, MIM 193700). However, mutations causing FSS have only been reported in MYH3. Herein we describe a Chinese DA family whose members meet classical strict criteria for FSS, as well as one member of the family who has isolated facial features consistent with FSS. No disease-causing mutation was found in MYH3. Segregation of microsatellite markers flanking the TNNI2 and TNNT3 genes at 11p15.5 was compatible with linkage. Subsequent sequencing of TNNI2 revealed a novel mutation, c.A493T (p.I165F), located in the C-terminal region, which is critical for proper protein function. This mutation was found to cosegregate with the FSS phenotype in this family, and assessment using SIFT and PolyPhen-2 predicted a damaging effect. To the best of our knowledge, we report the first TNNI2 mutation in classical FSS and describe an atypical adult FSS case with only facial contractures resulting from somatic mosaicism. We infer that DA1, DA2B and FSS represent a phenotypic continuum of the same disorder and provide further genetic evidence for this hypothesis.

Two Novel Mutations in Myosin Binding Protein C Slow Causing Distal Arthrogryposis Type 2 in Two Large Han Chinese Families May Suggest Important Functional Role of Immunoglobulin Domain C2

Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.

HLA‐B*35:168, a novel HLA allele identified in a Chinese platelet donor

HLA-B*35:168 has one nucleotide change from HLA-B*35:01:01:01 where 20 P is changed to R.HLA‐B*35:168 has one nucleotide change from HLA‐B*35:01:01:01 where 20 P is changed to R.

HLA-DRB1*11:106, a variant of HLA-DRB1*11, discovered in a Chinese bone marrow donor.

HLA-DRB1*11:106 has 1 nucleotide change from HLA-DRB1*11:01:01 at nucleotide 155 (G → A).

A new human leukocyte antigen class II allele, DRB1*09:12

HLA-DRB1*09:12 allele differs from HLA-DRB1*09:01:02 by a single nucleotide substitution at codon 41 (AAG → AAC).

A new HLA-A allele, HLA-A*11:120, sequenced in a Chinese hematopoietic stem cell donor

HLA‐A*11:120 has one nucleotide change from HLA‐A*11:01:01:01 where 295 T(ACC) is changed to S(AGC).

A novel HLA‐DRB1 allele, HLA‐DRB1*14:127:02, detected in a Chinese hematopoietic stem cell donor

HLA‐DRB1*14:127:02 has one nucleotide change from HLA‐DRB1*14:05:01 where Threonine (77) is changed to Asparagine.

HLA‐B*67:01:03, a HLA novel allele, identified in a Chinese platelet donor

HLA‐B*67:01:03 has one synonymous nucleotide change from HLA‐B*67:01:02 at nucleotide 873 (codon 267 Proline).