Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry

Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabi. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabi. Two main hypotheses can be considered for the origin of c.1187G > A: (i) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and (ii) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabi could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region

LipoDDx: a mobile application for identification of rare lipodystrophy syndromes

BACKGROUND: Lipodystrophy syndromes are a group of disorders characterized by a loss of adipose tissue once other situations of nutritional deprivation or exacerbated catabolism have been ruled out. With the exception of the HIV-associated lipodystrophy, they have a very low prevalence, which together with their large phenotypic heterogeneity makes their identification difficult, even for endocrinologists and pediatricians. This leads to significant delays in diagnosis or even to misdiagnosis. Our group has developed an algorithm that identifies the more than 40 rare lipodystrophy subtypes described to date. This algorithm has been implemented in a free mobile application, LipoDDx(R). Our aim was to establish the effectiveness of LipoDDx(R). Forty clinical records of patients with a diagnosis of certainty of most lipodystrophy subtypes were analyzed, including subjects without lipodystrophy. The medical records, blinded for diagnosis, were evaluated by 13 physicians, 1 biochemist and 1 dentist. Each evaluator first gave his/her results based on his/her own criteria. Then, a second diagnosis was given using LipoDDx(R). The results were analysed based on a score table according to the complexity of each case and the prevalence of the disease. RESULTS: LipoDDx(R) provides a user-friendly environment, based on usually dichotomous questions or choice of clinical signs from drop-down menus. The final result provided by this app for a particular case can be a low/high probability of suffering a particular lipodystrophy subtype. Without using LipoDDx(R) the success rate was 17 +/- 20%, while with LipoDDx(R) the success rate was 79 +/- 20% (p < 0.01). CONCLUSIONS: LipoDDx(R) is a free app that enables the identification of subtypes of rare lipodystrophies, which in this small cohort has around 80% effectiveness, which will be of help to doctors who are not experts in this field. However, it will be necessary to analyze more cases in order to obtain a more accurate efficiency value

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression

Measurement of charged particle spectra in minimum-bias events from proton-proton collisions at root s =13 TeV

Pseudorapidity, transverse momentum, and multiplicity distributions are measured in the pseudorapidity range vertical bar eta vertical bar 0.5 GeV in proton-proton collisions at a center-of-mass energy of root s = 13 TeV. Measurements are presented in three different event categories. The most inclusive of the categories corresponds to an inelastic pp data set, while the other two categories are exclusive subsets of the inelastic sample that are either enhanced or depleted in single diffractive dissociation events. The measurements are compared to predictions from Monte Carlo event generators used to describe high-energy hadronic interactions in collider and cosmic-ray physics.Peer reviewe