TRPS1 mutation associated with trichorhinophalangeal syndrome type 1 with 15 supernumerary teeth,hypoplastic mandibular condyles with slender condylar necks and unique hair morphology

Trichorhinophalangeal syndrome type 1 (TRPS1; Online Mendelian Inheritance in Man #190350) is an autosomal dominant disorder caused by mutations in TRPS1. We report a Thai male with TRPS1 who carried a c.1842C>T (p.Arg615Ter) mutation. He had 15 supernumerary teeth, double mental foramina, hypoplastic mandibular condyles with slender condylar necks and unique ultrastructural hair findings. Body hair was absent. The hair in the area of a congenital melanocytic nevus had a greater number of hair cuticles than normal. Occipital hair had abnormal hair follicles and cuticles. The scale edges of the hair cuticles were detached and rolled up. Hypoplastic mandibular condyles with slender condylar necks, double mental foramina and the rolled up edges of hair cuticles have not been reported in patients with TRPS1.     

Split hand-foot malformation and a novel WNT10B mutation

We report an Indian girl with split-hand/foot malformation (SHFM), sparse hair, and interrupted eyebrows, who carries a novel homozygous deletion c.695_697delACA in WNT10B. The variant is deduced to cause an in-frame deletion of Asn residue 232 (p.Asn232del). According to the protein model, this single amino acid deletion at the critical position in the protein structure is likely to severely affect the protein structure and function. This deletion is likely to lead decreased lifetime and make it unable to bind to its receptors and other ligands. The patient and all family members had normal bone density and they were not obese like some of the patients with WNT10B variants. Here we report a patient with SHFM6 who carried a novel WNT10B mutation. Sparse hair and interrupted eyebrows may be associated findings of SHFM6.     

ADAMTSL1 and mandibular prognathism

Mandibular prognathism is characterized by a prognathic or prominent mandible. The objective of this study was to find the gene responsible for mandibular prognathism. Whole exome sequencing analysis of a Thai family (family 1) identified the ADAMTSL1 c.176C>A variant as the potential defect. We cross-checked our exome data of 215 people for rare variants in ADAMTSL1 and found that the c.670C>G variant was associated with mandibular prognathism in families 2 and 4. Mutation analysis of ADAMTSL1 in 79 unrelated patients revealed the c.670C>G variant was also found in family 3. We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible. Adamtsl1 is strongly expressed in the condensed mesenchymal cells of the mouse condyle, but not at the cartilage of the long bones. This explains why the patients with ADAMTSL1 mutations had abnormal mandibles but normal long bones. This is the first report that mutations in ADAMTSL1 are responsible for the pathogenesis of mandibular prognathism.     

WNT10B mutations associated with isolated dental anomalies

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia‐associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.