Human Leukocyte Antigen Markers for Distinguishing Pustular Psoriasis and Adult-Onset Immunodeficiency with Pustular Reaction.

Pustular skin diseases, with pustular psoriasis (PP) being the prototype, are immune-mediated diseases characterized by the presence of multiple pustules, resulting from neutrophil accumulation in the layer of epidermis. Sterile skin pustular eruption, like PP, is also observed in 20-30% of patients with adult-onset immunodeficiency syndrome (AOID) and anti-interferon γ autoantibodies (IFN-γ), leading to challenges in classification and diagnosis. While the mechanism underlying this similar phenotype remains unknown, genetic factors in relation to the immune system are suspected of playing an important role. Here, the association between human leukocyte antigen (HLA) genes, which play essential roles in antigen presentation, contributing to immune response, and the presence of skin pustules in AOID and PP was revealed. HLA genotyping of 41 patients from multiple centers in Thailand who presented with multiple sterile skin pustules (17 AOID patients and 24 PP patients) was conducted using a next-generation-sequencing-based approach. In comparison to healthy controls, HLA-B*13:01 (OR = 3.825, 95%CI: 2.08-7.035), C*03:04 (OR = 3.665, 95%CI: 2.102-6.39), and DQB1*05:02 (OR = 2.134, 95%CI: 1.326-3.434) were significantly associated with the group of aforementioned conditions having sterile cutaneous pustules, suggesting a common genetic-related mechanism. We found that DPB1*05:01 (OR = 3.851, p = 0.008) and DRB1*15:02 (OR = 3.195, p = 0.033) have a significant association with pustular reaction in AOID patients, with PP patients used as a control. A variant in the DRB1 gene, rs17885482 (OR = 9.073, p = 0.005), was observed to be a risk factor for PP when using AOID patients who had pustular reactions as a control group. DPB1*05:01 and DRB1*15:02 alleles, as well as the rs17885482 variant in the DRB1 gene, were proposed as novel biomarkers to differentiate PP and AOID patients who first present with multiple sterile skin pustules without known documented underlying conditions.

LRP4 mutations, dental anomalies, and oral exostoses.

BACKGROUND: In order to generate a normal set of teeth, fine-tuning of Wnt/ß-catenin signaling is required, in which WNT ligands bind to their inhibitors or WNT inhibitors bind to their co-receptors. Lrp4 regulates the number of teeth and their morphology by modulating Wnt/ß-catenin signaling as a Wnt/ß-catenin activator or inhibitor, depending on its interactions with the partner proteins, such as Sostdc1 and Dkk1. AIM: To investigate genetic etiologies of dental anomalies involving LRP4 in a Thai cohort of 250 children and adults with dental anomalies. DESIGN: Oral and radiographic examinations and whole exome sequencing were performed for every patient. RESULTS: Two novel (p.Leu1356Arg and p.Ala1702Gly) and three recurrent (p.Arg263His, p.Gly1314Ser, and p.Asn1385Ser) rare variants in low-density lipoprotein receptor-related protein 4 (LRP4: MIM 604270) were identified in 11 patients. Oral exostoses were observed in five patients. CONCLUSION: Antagonism of Bmp signaling by Sostdc1 requires the presence of Lrp4. Mice lacking Lrp4 have been demonstrated to have alteration of Wnt-Bmp-Shh signaling and an abnormal number of incisors. Therefore, the LRP4 mutations found in our patients may disrupt Wnt-Bmp-Shh signaling, thereby resulting in dental anomalies and oral exostoses. Root maldevelopment in the patients suggests an important role of LRP4 in root morphogenesis.

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas.

BACKGROUND: Supernumerary teeth refer to extra teeth that exceed the usual number of dentitions. A mesiodens is a particular form of supernumerary tooth, which is located in the premaxilla region. The objective of the study was to investigate the genetic etiology of extra tooth phenotypes, including mesiodens and isolated supernumerary teeth. METHODS: Oral and radiographic examinations and whole-exome sequencing were performed on every patient in our cohort of 122 patients, including 27 patients with isolated supernumerary teeth and 94 patients with mesiodens. A patient who had multiple supernumerary teeth also had odontomas. RESULTS: We identified a novel (c.8498A>G; p.Asn2833Ser) and six recurrent (c.1603C>T; p.Arg535Cys, c.5852G>A; p.Arg1951His, c.6949A>T; p.Thr2317Ser; c.1549G>A; p.Val517Met, c.1921A>G; p.Thr641Ala, and c.850G>C; p.Val284Leu) heterozygous missense variants in FREM2 in eight patients with extra tooth phenotypes. CONCLUSIONS: Biallelic variants in FREM2 are implicated in autosomal recessive Fraser syndrome with or without dental anomalies. Here, we report for the first time that heterozygous carriers of FREM2 variants have phenotypes including oral exostoses, mesiodens, and isolated supernumerary teeth.

Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation.

A mesiodens is a supernumerary tooth located in the midline of the premaxilla. To investigate the genetic cause of mesiodens, clinical and radiographic examination were performed on 23 family members of a two-generation Hmong family. Whole exome sequencing (WES) or Sanger sequencing were performed in 22 family members and two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.

A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment.

BACKGROUND: Enamel knots and Hertwig epithelial root sheath (HERS) regulate the growth and folding of the dental epithelium, which subsequently determines the final form of tooth crown and roots. We would like to investigate the genetic etiology of seven patients affected with unique clinical manifestations, including multiple supernumerary cusps, single prominent premolars, and single-rooted molars. METHODS: Oral and radiographic examination and whole-exome or Sanger sequencing were performed in seven patients. Immunohistochemical study during early tooth development in mice was performed. RESULTS: A heterozygous variant (c. 865A>G; p.Ile289Val) in CACNA1S was identified in all the patients, but not in an unaffected family member and control. Immunohistochemical study showed high expression of Cacna1s in the secondary enamel knot. CONCLUSIONS: This CACNA1S variant seemed to cause impaired dental epithelial folding; too much folding in the molars and less folding in the premolars; and delayed folding (invagination) of HERS, which resulted in single-rooted molars or taurodontism. Our observation suggests that the mutation in CACNA1S might disrupt calcium influx, resulting in impaired dental epithelium folding, and subsequent abnormal crown and root morphology.

Rare Genetic Variants in Human APC Are Implicated in Mesiodens and Isolated Supernumerary Teeth.

The activation of Wnt/ß-catenin signalling is a prerequisite for odontogenesis. APC, a member of the AXIN-CK1-GSK3ß-APC ß-catenin destruction complex, functions to modulate Wnt/ß-catenin signalling to establish regular teeth number and positions. APC loss-of-function mutations are associated with the over-activation of WNT/ß-catenin signalling and subsequent familial adenomatous polyposis (FAP; MIM 175100) with or without multiple supernumerary teeth. The ablation of Apc function in mice also results in the constitutive activation of ß-catenin in embryonic mouse epithelium and causes supernumerary tooth formation. The objective of this study was to investigate if genetic variants in the APC gene were associated with supernumerary tooth phenotypes. We clinically, radiographically, and molecularly investigated 120 Thai patients with mesiodentes or isolated supernumerary teeth. Whole exome and Sanger sequencing identified three extremely rare heterozygous variants (c.3374T>C, p.Val1125Ala; c.6127A>G, p.Ile2043Val; and c.8383G>A, p.Ala2795Thr) in APC in four patients with mesiodentes or a supernumerary premolar. An additional patient with mesiodens was compound as heterozygous for two APC variants (c.2740T>G, p.Cys914Gly, and c.5722A>T, p.Asn1908Tyr). Rare variants in APC in our patients are likely to contribute to isolated supernumerary dental phenotypes including isolated mesiodens and an isolated supernumerary tooth.

Broad spectrum of anomalies including quadricuspid aortic valve associated with a novel frameshift SALL4 variant.

Each family member had a SALL4 variant. This is the first report of quadricuspid aortic valve and a genetic variant. The variation in phenotype caused by SALL4 mutations questions the division of SALL4-related phenotypes in three different entities.

SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease. METHODS: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed. RESULTS: WES identified three Thai patients presenting with similar pustular phenotypes-two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions. CONCLUSIONS: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms.

A Founder Intronic Variant in P3H1 Likely Results in Aberrant Splicing and Protein Truncation in Patients of Karen Descent with Osteogenesis Imperfecta Type VIII.

One of the most important steps in post-translational modifications of collagen type I chains is the hydroxylation of carbon-3 of proline residues by prolyl-3-hydroxylase-1 (P3H1). Genetic variants in P3H1 have been reported to cause autosomal recessive osteogenesis imperfecta (OI) type VIII. Clinical and radiographic examinations, whole-exome sequencing (WES), and bioinformatic analysis were performed in 11 Thai children of Karen descent affected by multiple bone fractures. Clinical and radiographic findings in these patients fit OI type VIII. Phenotypic variability is evident. WES identified an intronic homozygous variant (chr1:43212857A > G; NM_022356.4:c.2055 + 86A > G) in P3H1 in all patients, with parents in each patient being heterozygous for the variant. This variant is predicted to generate a new "CAG" splice acceptor sequence, resulting in the incorporation of an extra exon that leads to a frameshift in the final exon and subsequent non-functional P3H1 isoform a. Alternative splicing of P3H1 resulting in the absence of functional P3H1 caused OI type VIII in 11 Thai children of Karen descent. This variant appears to be specific to the Karen population. Our study emphasizes the significance of considering intronic variants.

Rare Variants in LRP4 Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans.

BACKGROUND: Low density lipoprotein receptor-related protein 4 (LRP4; MIM 604270) modulates WNT/ß-catenin signaling, through its binding of WNT ligands, and to co-receptors LRP5/6, and WNT inhibitors DKK1, SOSTDC1, and SOST. LRP4 binds to SOSTDC1 and WNT proteins establishing a negative feedback loop between Wnt/ß-catenin, Bmp, and Shh signaling during the bud and cap stages of tooth development. Consistent with a critical role for this complex in developing teeth, mice lacking Lrp4 or Sostdc1 have multiple dental anomalies including supernumerary incisors and molars. However, there is limited evidence supporting variants in LRP4 in human dental pathologies. METHODS: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice. RESULTS: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice. CONCLUSIONS: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/ß-catenin-BMP-SHH signaling.

DKK1 is a strong candidate for mesiodens and taurodontism.

A mutation in DKK1 gene leads to inhibitory DKK1 function, over-activation of WNT/ß-catenin signaling, disruptive development of dental epithelium, and subsequent mesiodens formation.

Subtotal Parathyroidectomy Successfully Controls Calcium Levels of Patients with Neonatal Severe Hyperparathyroidism Carrying a Novel CASR Mutation.

INTRODUCTION: Inactivating mutations of the calcium-sensing receptor (CASR) gene result in neonatal severe hyperparathyroidism (NSHPT). Total parathyroidectomy is an effective way to control life-threatening hypercalcemia in NSHPT but leads to permanent hypoparathyroidism. An alternative surgical option is subtotal parathyroidectomy. However, few cases were reported in the literature. Here, we report two unrelated NSHPT patients, one with a novel homozygous mutation (c.1817T>C; p.Leu606Pro) in CASRand the other with heterozygous for the same mutation who also carried two rare intronic variants in CASR. The outcomes of subtotal parathyroidectomy in these patients are also described. CASE PRESENTATION: Two infants presented with an alteration of consciousness, respiratory distress, and bradycardia. Severe hypercalcemia, hypophosphatemia, and markedly elevated parathyroid hormone levels were identified, suggesting NSHPT. Cinacalcet was unable to control calcium (Ca) levels of both patients. A novel heterozygous and homozygous missense mutation c.1817T>C; p.Leu606Pro was identified in patients 1 and 2, respectively. Based on the model prediction, proline substitution at Leu606 is likely to disrupt conversion between the active and inactive conformations at the extracellular to transmembrane domain interface of CASR. In addition, two extremely rare intronic variants in CASR (chr3:g.122180314A>G and chr3:g.122251601G>A, based on GRCh38) were identified in patient 1 and his mother. These variants might have contributed to the clinical manifestations of patient 1 who was heterozygous for the c.1817T>C; p.Leu606Pro variant. Subtotal parathyroidectomy was performed by removing three and a half parathyroid glands. So far, patient 1 has been in normocalcemia for 5 years. Patient 2 was in normocalcemia for 16 months after surgery and subsequently developed mild hypoparathyroidism which required only low-dose calcitriol treatment. CONCLUSION: We report a novel heterozygous and homozygous missense variant (c.1817T>C; p.Leu606Pro) in CASR in two NSHPT patients. The mutation likely disrupts conformational changes of CASR and results in cinacalcet unresponsiveness. Intronic variants in CASR identified in the patient with heterozygous variant might have contributed to the clinical manifestations of the patient. Although total parathyroidectomy is widely accepted as a standard treatment for NSHPT, we demonstrate that subtotal parathyroidectomy is also an effective procedure to normalize Ca levels and allow these patients to be in normocalcemia or mild hypoparathyroidism, which is simply controlled by low-dose calcitriol treatment. Subtotal parathyroidectomy appeared to be an effective treatment for NSHPT regardless of the molecular etiologies.

Core promoter in TNBC is highly mutated with rich ethnic signature.

The core promoter plays an essential role in regulating transcription initiation by controlling the interaction between transcriptional factors and sequence motifs in the core promoter. Although mutation in core promoter sequences is expected to cause abnormal gene expression leading to pathogenic consequences, limited supporting evidence showed the involvement of core promoter mutation in diseases. Our previous study showed that the core promoter is highly polymorphic in worldwide human ethnic populations in reflecting human history and adaptation. Our recent characterization of the core promoter in triple-negative breast cancer (TNBC), a subtype of breast cancer, in a Chinese TNBC cohort revealed the wide presence of core promoter mutation in TNBC. In the current study, we analyzed the core promoter in a Thai TNBC cohort. We also observed rich core promoter mutation in the Thai TNBC patients. We compared the core promoter mutations between Chinese and Thai TNBC cohorts. We observed substantial differences of core promoter mutation in TNBC between the two cohorts, as reflected by the mutation spectrum, mutation-effected gene and functional category, and altered gene expression. Our study confirmed that the core promoter in TNBC is highly mutable, and is highly ethnic-specific.

Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis.

BACKGROUND: Canonical and non-canonical WNT signaling are important for odontogenesis. WNT ligand secretion mediator (WLS; MIM611514) is required to transport lipid-modified WNT proteins from the Golgi to the cell membrane, where canonical and non-canonical WNT proteins are released into the extracellular milieu. Biallelic pathogenic variants in WLS are implicated in autosomal recessive Zaki syndrome (ZKS; MIM 619648), the only genetic condition known to be caused by pathogenic variants in WLS. OBJECTIVE: To investigate molecular etiology of dental anomalies in 250 patients with or without oral exostoses. PATIENTS AND METHODS: Clinical and radiographic examination, and whole exome sequencing, were performed in the case of 250 patients with dental anomalies with or without oral exostoses. RESULTS: Four extremely rare heterozygous missense variants (p.Ile20Thr, p.Met46Leu, p.Ser453Ile and p.Leu516Phe) in WLS were identified in 11 patients with dental anomalies. In five of these patients, a torus palatinus or a torus mandibularis was observed. CONCLUSION: We report for the first time the heterozygous WLS variants in patients with dental anomalies. Root maldevelopments in patients with WLS variants supports the role of canonical and non-canonical WNT signaling in root development. We also show that variants in WLS were implicated in torus palatinus and torus mandibularis. In addition, this is the first time that heterozygous carriers of WLS variants were found to manifest phenotypes. WLS variants were likely to have adverse effects on the concentration of WNT ligands delivered to the cell membrane, resulting in aberrant canonical and non-canonical WNT signaling, and subsequent phenotypes. LIMITATIONS OF THE STUDY: Patient's positioning during the acquisition of panoramic radiography might have affected the appearance of the tooth structures. If we had all family members of each patient to study co-segregation between genotype and phenotype, it would have strengthened the association of WLS variants and the phenotypes.

Novel Dental Anomaly-associated Mutations in WNT10A Protein Binding Sites.

OBJECTIVE: WNT/ß-catenin signaling is initiated by binding of a WNT protein to a Frizzled (FZD) receptor and a co-receptor, low-density lipoprotein (LDL) receptor-related protein 5 or 6 (LRP5/6). The objective of this study was to find the genetic variants responsible for dental anomalies found in 4 families. METHODS: Clinical and radiographic examination and whole exome sequencing were performed on 5 patients affected with dental anomalies and the mutant proteins modeled. RESULTS: Five patients were heterozygous for the WNT10A variants, including c.877C>T; p.Arg293Cys, c.874A>G; p.Ser292Gly, c.1042C>T; p.Arg348Cys, and c.1039G>T; p.347GluX. The p.Arg293Cys and p.Ser292Gly mutations are located in the WNT10A N-terminal domain region with binding sites for FZD receptor, porcupine, WNTLESS, and extracellular binding proteins, so they are likely to have adverse effects on binding these proteins. The p.Arg348Cys mutation, which is located in the binding site of LRP5/6 co-receptors, is postulated to result in impaired binding to these co-receptors. The nonsense mutation p.347GluX is predicted to result in the truncation of most of the C-terminal domain, which is likely to disrupt the binding of WNT10A to WNTLESS, the membrane protein that binds lipid-acylated WNT proteins to carry them from the endoplasmic reticulum to the cell surface and FZD. CONCLUSIONS: Four novel mutations in WNT10A were identified in patients with isolated tooth agenesis. The mutations in the N-terminal domain and the interface between the N- and C-terminal domains of WNT10A in our patients are likely to disrupt its binding with FZD, LRP5/6, and various other proteins involved in WNT10A processing and transport, impair WNT and SHH signaling, and subsequently result in tooth agenesis, microdontia, and root maldevelopment.

Clinical and Genetic Studies of the First Monozygotic Twins with Pfeiffer Syndrome.

Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and radiographic examination and whole exome sequencing were performed on two monozygotic twins with Pfeiffer syndrome. Results: An acceptor splice site mutation in FGFR2 (c.940-2A>G) was detected in both twins. The father and both twins shared the same haplotype, indicating that the mutant allele was from their father's chromosome who suffered severe upper airway obstruction and subsequent obstructive sleep apnea. Hypertrophy of nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Increased intracranial pressure in both twins were corrected early by fronto-orbital advancement with skull expansion and open osteotomy, in order to prevent the more severe consequences of increased intracranial pressure, including hydrocephalus, the bulging of the anterior fontanelle, and the diastasis of suture. Conclusions: Both twins carried a FGFR2 mutation and were discordant for lambdoid synostosis. Midface hypoplasia, narrow nasal cavities, and hypertrophic nasal turbinates resulted in severe upper airway obstruction and subsequent obstructive sleep apnea in both twins. Hypertrophy of the nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Fronto-orbital advancement with skull expansion and open osteotomy was performed to treat increased intracranial pressure in both twins. This is the first report of monozygotic twins with Pfeiffer syndrome.

Clinical Spectrum and Tumour Risk Analysis in Patients with Beckwith-Wiedemann Syndrome Due to CDKN1C Pathogenic Variants.

Beckwith-Wiedemann syndrome spectrum (BWSp) is an overgrowth disorder caused by imprinting or genetic alterations at the 11p15.5 locus. Clinical features include overgrowth, macroglossia, neonatal hypoglycaemia, omphalocele, hemihyperplasia, cleft palate, and increased neoplasm incidence. The most common molecular defect observed is hypomethylation at the imprinting centre 2 (KCNQ1OT1:TSS DMR) in the maternal allele, which accounts for approximately 60% of cases, although CDKN1C pathogenic variants have been reported in 5-10% of patients, with a higher incidence in familial cases. In this study, we examined the clinical and molecular features of all cases of BWSp identified by the Spanish Overgrowth Registry Initiative with pathogenic or likely pathogenic CDKN1C variants, ascertained by Sanger sequencing or next-generation sequencing, with special focus on the neoplasm incidence, given that there is scarce knowledge of this feature in CDKN1C-associated BWSp. In total, we evaluated 21 cases of BWSp with CDKN1C variants; 19 were classified as classical BWS according to the BWSp scoring classification by Brioude et al. One of our patients developed a mediastinal ganglioneuroma. Our study adds evidence that tumour development in patients with BWSp and CDKN1C variants is infrequent, but it is extremely relevant to the patient's follow-up and supports the high heterogeneity of BWSp clinical features associated with CDKN1C variants.

Mutations in LRP6 highlight the role of WNT signaling in oral exostoses and dental anomalies.

OBJECTIVE: The objective of this study was to investigate molecular etiologies of oral exostoses and dental anomalies in 14 patients from eight families. METHODS: Oral and radiographic examinations were performed on every patient. Whole exome and Sanger sequencing were performed on DNA of the patients, the unaffected parents and unaffected siblings. LRP6 mutant proteins were modeled and analyzed. RESULTS: Five mutations in LRP6, including four missense (p.Glu72Lys, p.Lys82Asn, Tyr418His, and p.Ile773Val) and one nonsense mutation (p.Arg32Ter), were identified. These mutations have not been reported to be associated with dental anomalies or oral exostoses. Oral features included a variety of oral exostoses (7 of the 14 patients), root defects (6 of the 14 patients), and tooth agenesis (5 of the 14 patients). Less common dental anomalies included microdontia, tooth fusion, odontomas, and mesiodens. Analysis of the protein models of the five LRP6 mutations shed light on their likely impact on LRP6 protein structure and function. CONCLUSION: Fourteen patients with five LRP6 mutations, including two recurrent mutations and three novel ones, are reported. Our study shows for the first time that mutations in LRP6 are associated with mesiodens, fusion of teeth, odontomas, microdontia, long roots, molars with unseparated roots, and taurodontism.

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses.

WNT/ß-catenin and BMP signaling pathways play important roles in the process of tooth development. Dysregulation of WNT/ß-catenin and BMP signaling is implicated in a number of human malformations, including dental anomalies. Whole exome and Sanger sequencing identified seven patients with LRP5 mutations (p.Asn1121Asp, p.Asp856Asn, p.Val1433Met, and p.Val1245Met) and six patients with BMP4 mutations (p.Asn150Lys, p.Gly168Arg, p.Arg269Gln, and p.Ala42Glu). All patients were affected with isolated dental anomalies (dental anomalies with no other structural defects), including mesiodens, tooth agenesis, unseparated roots, narrow roots, shortened and tapered roots, and taurodontism. Five patients with LRP5 and one with BMP4 mutations had oral exostoses. Protein models of LRP5 mutations indicate the possible functional effects of the mutations. Here we report for the first time that mutations in LRP5 are associated with dental anomalies. LRP5 appears to be the first gene related to pathogenesis of mesiodens. We also show for the first time that in addition to tooth agenesis, mutations in BMP4 are also implicated in root maldevelopment and torus mandibularis. Sharing of the phenotypes of the patients with LRP5 and BMP4 mutations, which include root maldevelopment, tooth agenesis, and torus mandibularis, implicates cross talks between the WNT/ß-catenin and BMP signaling pathways, especially during root development.

Expanding genotypic and phenotypic spectrums of LTBP3 variants in dental anomalies and short stature syndrome.

Mutations in LTBP3 are associated with Dental Anomalies and Short Stature syndrome (DASS; MIM 601216), which is characterized by hypoplastic type amelogenesis imperfecta, hypodontia, underdeveloped maxilla, short stature, brachyolmia, aneurysm and dissection of the thoracic aorta. Here we report a novel (p.Arg545ProfsTer22) and a recurrent (c.3107-2A > G) LTBP3 variants, in a Turkish family affected with DASS. The proband, who carried compound heterozygous variant c.3107-2A > G, p.Arg545ProfsTer22, was most severely affected with DASS. The proband's father, who carried the heterozygous variant c.3107-2A > G had short stature and prognathic mandible. The mother and brother of the proband carried the heterozygous variant p.Arg545ProfsTer22, but only the mother showed any DASS characteristics. The c.3107-2A > G and the p.Arg545ProfsTer22 variants are expected to result in abnormal LTPB3 protein, failure of TGFß-LAP-LTBP3 complex formation, and subsequent disruption of TGFß secretion and activation. This is the first report of heterozygous carriers of LTBP3 variants showing phenotypes. The new findings of DASS found in this family include taurodontism, single-rooted molars, abnormal dentin, calcified dental pulp blood vessels, prognathic mandible, failure of mandibular tooth eruption, interatrial septal aneurysm, secundum atrial septal defect, tricuspid valve prolapse, and a recurrent glenohumeral joint dislocation.