Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling

Dufour, William; Alawbathani, Salem; Jourdain, Anne‐Sophie; Asif, Maria; Baujat, Geneviève; Becker, Christian; Budde, Birgit; Gallacher, Lyndon; Georgomanolis, Theodoros; Ghoumid, Jamal; Höhne, Wolfgang; Lyonnet, Stanislas; Ba-Saddik, Iman Ali; Manouvrier‐Hanu, Sylvie; Motameny, Susanne; Noegel, Angelika A.; Pais, Lynn; Vanlerberghe, Clémence; Wagle, Prerana; White, Susan; Willems, Marjolaine; Nürnberg, Peter; Escande, Fabienne; Petit, Florence; Hussain, Muhammad Sajid

doi:10.1016/j.gim.2022.04.022

Cited by 7 publications

(4 citation statements)

References 33 publications

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“…Studies have suggested an association between monoallelic/ biallelic loss-of-function variants in LEF1 and ectodermal dysplasia [3,4]. Our patient did not show any symptoms associated with ectodermal dysplasia.…”

supporting

confidence: 40%

The First Case of Congenital Nephrogenic Diabetes Insipidus Caused by AVPR2 Disruption Because of 4q25 Insertional Translocation

Kim,

Ahn,

Park

et al. 2023

Ann Lab Med

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Letter to the Editor Diagnostic GeneticsDear Editor, Congenital nephrogenic diabetes insipidus (NDI) is characterized by an impaired renal response to arginine vasopressin (AVP) [1]. Approximately 90% of patients with NDI have mutations in the AVP receptor 2 gene (AVPR2) [2]. Mutations in AVPR2 located in chromosome X result in X-linked NDI, which presents characteristic symptoms, including polyuria, polydipsia, and fever in male infants.A two-month-old boy (Pt #1) presented to Seoul National University Hospital with irritability, polyuria, and mild fever in March 2023. Informed consent was obtained from the patient's guardian. During a water deprivation test, he exhibited an elevated serum sodium level and a continuous decrease in urine osmolality, which were not alleviated by subcutaneous vasopressin injection. The family history indicated X-linked recessive inheritance (Fig. 1A). The patient's second uncle (Pt #2) with similar symp-tom as his nephew had also been diagnosed as having NDI as an infant.We performed whole-exome sequencing of a blood sample of Pt #2. A soft-clipped region was observed in intron 2 of AVPR2, using Integrative Genomics Viewer (Fig. 1B). Analysis of chimeric reads revealed a putative chromosomal translocation between the long arms of chromosome 4 and chromosome X. Primers for the suspected breakpoints were designed, and PCR was performed. Subsequent Sanger sequencing revealed breakpoints at chrX:153,170,697 and chr4:109,062,641 (Fig. 1C). Karyotyping was performed to confirm the translocation. Surprisingly, chromosomal analysis revealed normal findings (data not shown). Subsequently, a chromosomal microarray assay was performed on peripheral blood from Pt #1, using the CytoScan Dx Assay

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supporting

confidence: 40%

The First Case of Congenital Nephrogenic Diabetes Insipidus Caused by AVPR2 Disruption Because of 4q25 Insertional Translocation

Kim,

Ahn,

Park

et al. 2023

Ann Lab Med

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“…Ectodermal dysplasias (ED) is a family of genetic skin diseases in which the common clinical sign is hypertrichosis, and inactivation of Lef1 targeting in mice leads to complete blockage of ectodermal development [ 42 ]. A new study confirmed that single allele and double allele variants in Lef1 are the etiology of a new syndrome leading to ED [ 43 ]. Hutchinson–Gilford progeria syndrome (HGPS) is a deleterious premature aging disease with common clinical symptoms of alopecia and skin sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Lef1 and Dlx3 May Facilitate the Maturation of Secondary Hair Follicles in the Skin of Gansu Alpine Merino

Sun

et al. 2022

Genes

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Lymphatic enhancer factor 1 (Lef1) and distal-less homeobox 3 (Dlx3) are the transcription factors involved in regulating hair follicle development in mice, goats, and other animals. Their deletion can lead to hair follicle deficiency. In this study, hematoxylin–eosin staining (HE), real-time quantitative PCR (RT-qPCR), immunohistochemistry, and immunofluorescence were used to analyze the expression, location, and biological functions of Lef1 and Dlx3 in the lateral skin of Gansu Alpine Merino aged 1, 30, 60, and 90 days. The results revealed that the number of hair follicles decreased with age and was significantly higher at 1 day than in the other three age groups (p < 0.05). The mRNA levels of Lef1 and Dlx3 in the skin of 30-day old Gansu Alpine Merino were significantly higher than those in the other three age groups (p < 0.05). Protein expression of Lef1 and Dlx3 was lowest at 1 day (p < 0.05) and peaked at 60 days. Lef1 and Dlx3 exhibited a high density and strong positive expression in the dermal papillae; additionally, Dlx3 exhibited a high density and strong positive expression in the inner and outer root sheaths. Collectively, Lef1 and Dlx3 may facilitate the maturation of secondary hair follicles, which is mainly achieved through the dermal papillae and inner and outer root sheaths.

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“…Recently, de novo microdeletions encompassing the LEF1 gene have also been identified in two unrelated patients with severe oligodontia and other features compatible with hypohidrotic ectodermal dysplasia [ 32 ]. In addition, monoallelic and biallelic LEF1 variants have been proposed as causative factors for a putatively novel syndrome characterized by limb malformations and ectodermal dysplasia [ 33 ]. It is worth noting that the heterozygous LEF1 missense variant (p.Lys95Asn) identified in the current study was found in an individual with a mild form of sporadic TA.…”

Section: Discussionmentioning

confidence: 99%

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

Biedziak

Firlej

Dąbrowska

et al. 2022

JCM

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Non-syndromic tooth agenesis (ns-TA) is one of the most common dental anomalies characterized by the congenital absence of at least one permanent tooth (excluding third molars). Regarding the essential role of genetic factors in ns-TA aetiology, the present study aimed to identify novel pathogenic variants underlying hypodontia and oligodontia. In a group of 65 ns-TA patients and 127 healthy individuals from the genetically homogenous Polish population, the coding sequences of 423 candidate genes were screened using targeted next-generation sequencing. Pathogenic and likely pathogenic variants were identified in 37 (56.92%) patients, including eight nucleotide alternations of genes not previously implicated in ns-TA (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22 and TP63). However, since only single variants were detected, future research is required to confirm and fully understand their role in the aetiology of ns-TA. Additionally, our results support the importance of already known ns-TA candidate genes (AXIN2, EDA, EDAR, IRF6, LAMA3, LRP6, MSX1, PAX9 and WNT10A) and provide additional evidence that ns-TA might be an oligogenic condition involving the cumulative effect of rare variants in two or more distinct genes.

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Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling

Cited by 7 publications

References 33 publications

The First Case of Congenital Nephrogenic Diabetes Insipidus Caused by AVPR2 Disruption Because of 4q25 Insertional Translocation

The First Case of Congenital Nephrogenic Diabetes Insipidus Caused by AVPR2 Disruption Because of 4q25 Insertional Translocation

Lef1 and Dlx3 May Facilitate the Maturation of Secondary Hair Follicles in the Skin of Gansu Alpine Merino

Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing

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