A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay.

We report a Japanese patient with tall stature, dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction, bilateral entropion of both eyelids, high arched palate, long fingers, and mild hyperextensible finger joints as a case of Marfanoid-progeroid-lipodystrophy syndrome. Genetic investigation revealed a heterozygous variant NC_000015.10(NM_000138.5):c.8226+5G>A in the FBN1 gene. Skipping of exon 65 and escaping nonsense-mediated decay followed by frameshift were experimentally confirmed in the proband's mRNA.

A novel nonsense variant in ARID1B causing simultaneous RNA decay and exon skipping is associated with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband's clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype.

Novel USP9X variants in two patients with X-linked intellectual disability.

USP9X variants have been reported in patients with X-linked intellectual disability. Here, we report two female patients with intellectual disability and pigment abnormalities along Blaschko lines. Targeted resequencing identified two novel heterozygous variants, c.4068_4072del (p. (Leu1357Tyrfs*12)) and c.1201C>T (p. (Arg401*)), in USP9X. Our findings provide further evidence that USP9X variants cause intellectual disability.

Correction: Nationwide survey for current clinical status of amniocentesis and maternal serum marker test in Japan.

Since the publication of this paper, the authors noticed that Yosuke Fujii was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.

Nationwide survey for current clinical status of amniocentesis and maternal serum marker test in Japan.

Prenatal testing has been provided in Japan over the past several decades. However, it is difficult to assess the clinical status of amniocentesis (AC) and maternal serum markers (MSM) because obstetricians can perform these tests without registration. This study aims to investigate the current clinical status of AC and MSM in Japan. We conducted a questionnaire study that was intended for a total of 5622 Japanese obstetrics/gynecology facilities during October 2013 to January 2014. The response rate was 40.8% (2295/5622). Of the 2295 facilities, 864 performed MSM (37.7%), 619 performed AC (27.0%) and 412 performed both (18.0%). The average number of MSM tests was 2.0 per month (range 0-52), and the average number of AC tests was 2.4 per month (range 0-30). Involvement of genetic professionals, such as clinical geneticists (CGs) and certified genetic counselors (CGCs), contribute to a content-rich explanation and management of difficult issues and lengthened the explanation time. Nevertheless, relatively few facilities employed these specialists (MSM: 96/864 and AC: 128/619). This is the first study to highlight the current clinical status of AC and MSM tests in Japan. Active involvement of CGs and CGCs can provide more appropriate genetic counseling for prenatal tests.

Ehlers-Danlos syndrome, vascular type: a novel missense mutation in the COL3A1 gene.

We report a 34-year-old Japanese female with the vascular type of Ehlers-Danlos syndrome. She had thin translucent skin, extensive bruising, toe joint hypermobility, left lower extremity varicose veins, and chronic wrist, knee and ankle joint pain. She also had dizziness caused by autonomic dysfunction. Magnetic resonance angiography showed tortuous vertebral and basilar arteries, mild left carotid canal bulging, and right anterior tibial artery hypoplasia. Electron microscopic examinations of a skin biopsy revealed extremely dilated rough endoplasmic reticulum in dermal fibroblasts and wide variability of individual collagen fibril diameters. A molecular analysis using a conventional total RNA method and a high-resolution melting curve analysis using genomic DNA revealed a novel missense mutation within exon 48 of the COL3A1 gene, c.3428G>A, leading to p.Gly1143Glu.

Associations of blood selenium and serum lipid levels in Japanese premenopausal and postmenopausal women.

OBJECTIVE: The purpose of this study was to investigate whether the level of selenium in serum or the level of selenium in erythrocytes (E-Se) was associated with serum lipid parameters (total cholesterol [TC], triglycerides, and high-density and low-density lipoprotein cholesterol [LDL-C]) in pre- and postmenopausal women. DESIGN: Healthy female workers aged 35 to 60 years were recruited, and TC, triglycerides, high-density lipoprotein cholesterol, LDL-C, E-Se, and serum-Se levels were measured in 68 premenopausal and 59 postmenopausal women after excluding those who were treated for hyperlipidemia, receiving hormone therapy, had previous gynecological surgeries, or had irregular menstrual cycles. Information on these women, such as smoking status, current status of menstruation, and current or previous medical treatments, was obtained from a self-administered questionnaire. Correlation analyses and stepwise multiple regression analysis were applied to reveal the interrelationship between serum lipids and Se levels after adjusting for age, body mass index, smoking, and menopause status. RESULTS: Postmenopausal women had significantly higher levels of TC, triglycerides, and LDL-C and lower levels of E-Se than premenopausal women. TC and LDL-C levels after menopause correlated negatively with E-Se. These associations were also statistically significant after controlling for age, smoking status, and body mass index. E-Se was selected as a significant related variable to explain TC and LDL-C levels as well as body mass index by multiple regression analysis. CONCLUSION: E-Se may be one of the possible associated factors that decrease the levels of TC and LDL-C after menopause. Further studies are needed to clarify the cause-and-effect relationship of nutritional Se status and lipid profile.

[An evaluation of teaching objectives for seminars and clerkship of social medicine in medical schools in Japan].

OBJECTIVES: The purpose of this study was to evaluate the curriculum of seminars and clerkship for social medicine in medical schools in Japan, with special reference to teaching objectives. METHODS: A survey was conducted in December, 2002 by sending questionnaires to all the member departments of the Conference for Hygiene and Public Health Teaching in Medical Schools in Japan. Teaching objectives for seminars and clerkship of social medicine stated in their curricula were analyzed by frequencies of key words related to learner's "Knowledge, Attitude, and Behavior". Also, five professors of public health independently rated the stated teaching objectives using nine evaluation criteria divided into three levels and mean ratings were obtained. RESULTS: Although 80% of the schools described their General Instructional Objectives (GIOs), only 63% of the universities stated Specific Behavioral Objectives (SBOs). Evaluation of the contents of the descriptions revealed that, although many courses described the GIOs with the student as subjective, only a small number of courses mentioned "Attitude and Behavior" in SBO. Also, many courses did not make any apparent distinction between GIOs and SBOs. CONCLUSIONS: Practical training is a crucial component in medical education and seminars and clerkship play an important role in teaching social medicine to medical students. However, the present study revealed that many medical schools in Japan do not have adequately defined teaching objectives. Improvement of the curricula in courses of social medicine is required with particular reference to specific behavioral objectives and goals for seminars and clerkship.

True hermaphroditism with 46,X,+22p/46,XY and gonadal mosaicism detected by fluorescence in situ hybridization.

A Japanese girl was diagnosed as true hermaphroditism with 46,X,+mar/46,XY and the marker chromosome was determined on the short arm of chromosome 22 without alpha-satellite by fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) methods. At birth, she showed intersexual external genitalia, urethral-vaginal fistula and right inguinal hernia. The right gonad was revealed as an ovotestis, and the left was as an undifferentiated testis. The gonadal mosaicism was demonstrated directly in gonadal tissue by interphase FISH.