Formulation of the Comfort Women Discourse in International Society

Cystic fibrosis (CF) causes a relatively high medical consumption. A large part of the treatment takes place at home. Because data regarding nonhospital care are lacking, we wished to determine the costs of care of patients with CF outside the hospital. A questionnaire was sent to 73 patients with CF from two Dutch hospitals (response rate 64%, 14 children and 33 adults). Average consumption and average costs per patient per year were calculated for children and adults for six categories: non-hospital medical care; domestic help; diet; travelling because of CF; medication; and devices and special facilities at home, work or school. The average non-hospital costs of care amounted to £4,641 per child per year (range £712-13,269) and £10,242 per adult (range £1,653-26,571). Nonhospital medical care for children and adults accounted for, respectively, 8 and 5% of these costs, domestic help for 15 and 9%, diet for 10 and 7%, travelling because of CF for 4 and 8%, medication for 63 and 67%, and devices and special facilities at home, work or school for 1 and 4%. Nonhospital costs of care of cystic fibrosis are very high and amount to 50% of the total (medical and nonmedical) lifetime costs of cystic fibrosis

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal-contractile coupling

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function

Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

published_or_final_versio

MENDELIAN PHENOTYPES IN THE NETHERLANDS

We report here a database listing Mendelian phenotypes described in the Netherlands and/or in populations originating from this country, and describe the results of a quantitative analysis of the database. The database is specifically directed at the presence, frequency and origin of the phenotypes. These are arranged according to their mode of inheritance: autosomal dominant (AD), autosomal recessive (AR) and X-linked. Only those phenotypes which have been reported in accessible sources were included. We entered 1,482 references up to January 1, 1991. At least 672 different loci were decribed in the Netherlands at this date: 321 (47.8%) AD, 283 (42.1%) AR and 68 (10.1%) X-linked. Almost 2.5% of all loci in our database have no comparable entry in McKusick [Mendelian Inheritance in Man, ed 9. Baltimore, The Johns Hopkins University Press, 19901 (MIM). There is a significant difference (p <0.01) according to the division into AD, AR, and X-linked phenotypes between our database and MIM, in which 61.7% of the phenotypes are AD, 31.5% AR and 6.8% X-linked. Dutch prevalence data for 38 monogenic disorders and 24 polymorphic systems are listed