A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans.

Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment.

Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.

BACKGROUND: The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype. METHODS: We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening. RESULTS: We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes. CONCLUSION: The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.

GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient.

BACKGROUND: GATA transcription factors are evolutionary conserved zinc finger proteins with multiple roles in cell differentiation/proliferation and organogenesis. GATA5 is only transiently expressed in the embryonic heart, and the inactivation of both Gata5 alleles results in a partially penetrant bicuspid aortic valve (BAV) phenotype in mice. We hypothesized that only biallelic mutations in GATA5 could be disease causing. METHODS: A total of 185 patients with different forms of congenital heart disease (CHD) were screened along 150 healthy individuals for GATA4, 5, and 6. All patients' phenotypes were diagnosed with echocardiography. RESULTS: Sequencing results revealed eight missense variants (three of which are novel) in cases with various conotruncal and septal defects. Out of these, two were inherited in recessive forms: the p.T67P variant, which was found both in patients and in healthy individuals, and the previously described p.Y142H variant which was only found in a patient with a double outlet right ventricle (DORV). We characterized the p.Y142H variant and showed that it significantly reduced the transcriptional activity of the protein over cardiac promoters by 30-40%. CONCLUSION: Our results do prove that p.Y142H is associated with DORV and suggests including GATA5 as a potential gene to be screened in patients with this phenotype.