Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis

Qualitative investigation of the factors that generate ambivalent feelings in women who give birth after receiving negative results from non-invasive prenatal testing

Background: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. Methods: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. Results: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. Conclusions: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women

Peran Mutasi Gen CRELD1 pada Defek Septum Ventrikel dan Hubungannya dengan Manifestasi Klinis

Latar belakang. Defek septum ventrikel (DSV) merupakan salah satu jenis penyakit jantung bawaan (PJB) yang paling sering ditemukan. Etiologi DSV berhubungan dengan faktor genetik, nongenetik, atau interaksi antara faktor genetik dan nongenetik. Gen CRELD1 adalah suatu gen yang terletak pada kromosom 3p25. Mutasi gen CRELD1 akan menyebabkan gangguan pada pembentukan septum interventrikular. Tujuan. Mengetahui peran mutasi gen CRELD1 pada DSV dan hubungannya dengan manifestasi klinis. Metode. Subjek penelitian adalah 61 pasien DSV dan 110 pasien kontrol tanpa PJB yang memenuhi kriteria inklusi. Deteksi mutasi gen CRELD1 dilakukan dengan pemeriksaan sekuensing terhadap isolasi DNA. Hasil. Ditemukan satu anak dengan mutasi CRELD1, mutasi yang terjadi adalah missense mutations dan tempat mutasi terletak pada ekson 10 c.1136T>C (p. Met379Thr). Mutasi tersebut tidak ditemukan pada kontrol. Mutasi gen CRELD1 terjadi pada anak dengan DSV inlet besar dan disertai hipertensi pulmonal. Ditemukan empat tempat mutasi SNPs, tiga di antaranya telah dilaporkan ke gene Bank sebagai SNPs, dan satu tempat mutasi belum pernah dilaporkan. Kesimpulan. Didapatkan mutasi gen CRELD1 pada DSV inlet besar dan hipertensi pulmonal, sehingga perlu segera dilakukan penutupan defek ventrikel. Maka adanya mutasi gen CRELD1 dapat digunakan sebagai deteksi dini dan tata laksana yang lebih baik terhadap DSV

SMOC1 Is Essential for Ocular and Limb Development in Humans and Mice

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinomaResearch in context

Summary: Background: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. Methods: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. Findings: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. Interpretation: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. Funding: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research