Refining the clinical phenotype associated with missense variants in exons 38 and 39 of KMT2D.

Loss-of-function variants in KMT2D are responsible for Kabuki syndrome type 1 (KS1). In the last 5 years, missense variants in exon 38 or 39 in KMT2D have been found in patients exhibiting a new phenotype with multiple malformations and absence of intellectual disability, distinct from KS1. To date, only 16 cases have been reported with classic features of hearing loss, abnormality of the ear, lacrimal duct defects, branchial sinus/neck pits, choanal atresia (CA), athelia, hypo(para)thyroidism, growth delay, and dental anomalies. We report here two families and one unpublished variant, refining the clinical and molecular knowledge on this new entity. Family 1 presented with apparently isolated autosomal dominant choanal atresia, in eight members across three generations. Exome sequencing (ES) in the proband and one cousin revealed a p.Glu3569Gly variant in exon 38 of KMT2D, segregating with choanal atresia in the family. Clinical reevaluation evidenced thyroid dysfunction, mild hearing anomalies, and hypoplastic nipple in some patients. Family 2 presented with nasolacrimal duct obstruction, hearing loss, mild facial features, unilateral axial polydactyly, and unilateral toe V-VI syndactyly. ES revealed a de novo already reported p.Arg3582Gln variant in exon 38 of KMT2D. Considering these results and the existing literature, we suspect that missense variants in exon 38 of KMT2D are responsible for phenotypes that are even milder (isolated CA) and broader (polydactyly) than what has been previously described.

Screening for Retinopathy of Prematurity: Insight into Optimizing Screening.

PURPOSE: To determine the factors influencing the time from preterm birth and retinopathy of prematurity (ROP) detection to optimize the timing of the initial screening. METHODS: This multicenter retrospective study enrolled preterm infants born before 32 weeks of gestational age (GA) and/or weighing less than 1,500 g between January 1, 2011, and December 31, 2015. ROP screening was performed using fundus photography with a wide-field camera. Population and follow-up characteristics were recorded. RESULTS: Among the 1,266 preterm infants observed, 795 were retained for analysis. One hundred seventy-four (21.6%) cases of ROP were detected with the first examination performed at 32.3 ± 1.6 weeks of postmenstrual age (PMA) and 5.4 ± 1.0 weeks of postnatal age (PNA). The first signs of ROP were detected at 34.0 ± 1.9 weeks of PMA and 7.2 ± 1.8 weeks of PNA, respectively. In the multivariate analysis, an older GA, a longer duration of mechanical ventilation, and a lower birth weight were correlated with a longer time between preterm birth and ROP detection (p < 0.0001, p < 0.0001, and p = 0.0359, respectively). CONCLUSION: The first examination for ROP screening should be individualized to fit the first screening examination as closely as possible to the first signs of ROP in order to avoid unnecessary examinations without missing ROP.

Modification of erythrocyte membrane phospholipid composition in preterm newborns with retinopathy of prematurity: The omegaROP study.

N-3 polyunsaturated fatty acids (PUFAs) may prevent retinal vascular abnormalities observed in oxygen-induced retinopathy, a model of retinopathy of prematurity (ROP). In the OmegaROP prospective cohort study, we showed that preterm infants who will develop ROP accumulate the n-6 PUFA arachidonic acid (ARA) at the expense of the n-3 PUFA docosahexaenoic acid (DHA) in erythrocytes with advancing gestational age (GA). As mice lacking plasmalogens -That are specific phospholipids considered as reservoirs of n-6 and n-3 PUFAs- Display a ROP-like phenotype, the aim of this study was to determine whether plasmalogens are responsible for the changes observed in subjects from the OmegaROP study. Accordingly, preterm infants aged less than 29 weeks GA were recruited at birth in the Neonatal Intensive Care Unit of University Hospital Dijon, France. Blood was sampled very early after birth to avoid any nutritional influence on its lipid composition. The lipid composition of erythrocytes and the structure of phospholipids including plasmalogens were determined by global lipidomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). LC-HRMS data confirmed our previous observations by showing a negative association between the erythrocyte content in phospholipid esterified to n-6 PUFAs and GA in infants without ROP (rho = -0.485, p = 0.013 and rho = -0.477, p = 0.015 for ethanolamine and choline total phospholipids, respectively). Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) species with ARA, namely PtdCho16:0/20:4 (rho = -0.511, p < 0.01) and PtdEtn18:1/20:4 (rho = -0.479, p = 0.015), were the major contributors to the relationship observed. On the contrary, preterm infants developing ROP displayed negative association between PtdEtn species with n-3 PUFAs and GA (rho = -0.380, p = 0.034). They were also characterized by a positive association between GA and the ratio of ethanolamine plasmalogens (PlsEtn) with n-6 PUFA to PlsEtn with n-3 PUFAs (rho = 0.420, p = 0.029), as well as the ratio of PlsEtn with ARA to PlsEtn with DHA (rho = 0.843, p = 0.011). Altogether, these data confirm the potential accumulation of n-6 PUFAs with advancing GA in erythrocytes of infants developing ROP. These changes may be partly due to plasmalogens.

Alteration of erythrocyte membrane polyunsaturated fatty acids in preterm newborns with retinopathy of prematurity.

Extremely preterm infants are at high risk for retinopathy of prematurity (ROP), a potentially blinding disease characterized by abnormalities in retinal vascularization. Whereas animal studies revealed that n-3 polyunsaturated fatty acids (PUFAs) may be of benefit in preventing ROP, human studies conducted on preterm infants during the 1st weeks of life showed no association between blood n-3 PUFA bioavailability and ROP incidence and/or severity, probably because of the influence of nutrition on the lipid status of infants. In the OmegaROP prospective cohort study, we characterized the erythrocyte concentrations of PUFAs in preterm infants aged less than 29 weeks gestational age (GA) without any nutritional influence. We show that GA is positively associated with the erythrocyte n-6 to n-3 PUFA ratio, and particularly with the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA), in infants with ROP. A time-dependent accumulation of AA at the expense of DHA seems to occur in utero in erythrocytes of preterm infants who will develop ROP, thus reinforcing previous data on the beneficial properties of DHA on this disease. In addition, preliminary data on maternal erythrocyte membrane lipid concentrations suggest modifications in placental transfer of fatty acids. Documenting the erythrocyte AA to DHA ratio at birth in larger cohorts might be useful to set up new prognostic factors for ROP.