Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss-of-function vs missense variants.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent, complex congenital malformation. Genome-wide association studies (GWAS) on NSCL/P have consistently identified association for the 1p22 region, in which ARHGAP29 has emerged as the main candidate gene. ARHGAP29 re-sequencing studies in NSCL/P patients have identified rare variants; however, their clinical impact is still unclear. In this study we identified 10 rare variants in ARHGAP29, including five missense, one in-frame deletion, and four loss-of-function (LoF) variants, in a cohort of 188 familial NSCL/P cases. A significant mutational burden was found for LoF (Sequence Kernel Association Test, p = 0.0005) but not for missense variants in ARHGAP29, suggesting that only LoF variants contribute to the etiology of NSCL/P. Penetrance was estimated as 59%, indicating that heterozygous LoF variants in ARHGAP29 confer a moderate risk to NSCL/P. The GWAS hits in IRF6 (rs642961) and 1p22 (rs560426 and rs4147811) do not seem to contribute to the penetrance of the phenotype, based on co-segregation analysis. Our data show that rare variants leading to haploinsufficiency of ARHGAP29 represent an important etiological clefting mechanism, and genetic testing for this gene might be taken into consideration in genetic counseling of familial cases.

Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X(7), encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X(7) has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004

Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure.

Nine infants chronically exposed to methadone in utero were studied from birth to 7 weeks of age (66 studies). The maternal dose of methadone/HCl during the third trimester ranged from 14 to 70 mg orally once a day. The mean (range) of serum methadone t 1/2 in the neonates was 53 hours (22 to 113). In the first four days of life the methadone-exposed infants had a significantly (P less than 0.005) decreased sensitivity to carbon dioxide compared to control infants as measured by the slope of the ventilatory response curve. The mean slope +/- SD for the methadone-exposed infants, 10.4 +/- 7.7 ml/minute/kg mm Hg, was one third that of the control group (30.0 +/- 9.9 ml/minute/kg/mm Hg). Total ventilation, respiratory frequency, oxygen consumption, and end-tidal PCO2 were not significantly different in the two groups. The depressed ventilatory response to carbon dioxide persisted for an average of 15 days and lasted as long as 31 days in one infant. The time required to achieve a normal slope was not related to the size of the maternal methadone dose, to neonatal serum methadone t 1/2, or to the severity of and therapy for methadone withdrawal. If this abnormality in sensitivity to carbon dioxide persists beyond the neonatal period in some infants, it may contribute to the increased incidence of the sudden infant death syndrome among infants exposed to methadone in utero. Measurement of the ventilatory response to carbon dioxide may be clinically useful to determine which of these infants are at risk for SIDS.

Percutaneous cardiac catheterization and atrial balloon septostomy in pediatrics.

Between November, 1971, and July, 1975, 688 patients ranging in age from six hours to 21 years have undergone percutaneous transfemoral venous and/or arterial catheterization at the University of Oregon Health Sciences Center. This represents 93% of all venous catheterizations of the right side of the heart and 97% of all arterial catheterizations of the left side of the heart in the pediatric age range. One hundred and ninety-five patients (29% of the group) weighed 5 kg or less and 133 (20% of the group) were neonates. There were virtually no complications following the venous studies. The complication rate following percutaneous arterial studies is lower than is the reported experience with cut-down arteriotomies. Long-term survival following percutaneous atrial balloon septostomy in D-transposition of the great arteries was comparable to that following cut-down balloon septostomy. The ease of accomplishment, significantly lower complication rate, and successful accomplishment of atrial balloon septostomy prompt us to advocate that the percutaneous technique of cardiac catheterization be extended to include the neonate and young infant who weighsless than 5 kg.