Characterisation of the clinical phenotype in Phelan-McDermid syndrome

Background Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. Methods We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. Results We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. Conclusions This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

History of mutation breeding and molecular research using induced mutations in Japan.

Following the construction of the Gamma Field at the Institute of Radiation Breeding in 1960, mutation breeding was accelerated in Japan. The facility is used, with a radiation dose up to 2 Gy/day (ca. 300,000 times that of natural background), to induce mutations at a higher frequency than occurs in nature. There have been 318 direct- use mutant cultivars representing 79 species generated through irradiation of gamma-rays, X-rays, ion beams and chemicals and somaclonal variation. Approximately 79% of these direct-use cultivars were induced by radiation. There have been 375 indirect-use mutant cultivars, including 332 rice, of which 162 cultivars (48.8%) were derived from the semi-dwarf mutant cv. 'Reimei'. The economic impact of these mutant cultivars, primarily of rice and soybean, is very large. Some useful mutations are discussed for rice, such as low digestible protein content, low amylose content, giant embryo and non-shattering. Useful mutations in soybean such as radiosensitivity, fatty acid composition and super-nodulation have been identified. Japanese pear and apple resistant to Alternaria disease have also been identified. The achievements of biological research such as characterization and determination of deletion size generated by gamma-rays, the effect of deletion size and the location, and a mechanism of dominant mutation induction are identified. Similarly, genetic studies on mutations generated through the use of gamma-ray induced mutations, such as phytochrome response, aluminium tolerance, stay-green (Mendel's gene) and epicuticular wax have also been conducted. Mutation breeding is a very useful technology for isolating genes and for elucidating gene functions and metabolic pathways in various crops.

Narrowing down the region responsible for 1q23.3q24.1 microdeletion by identifying the smallest deletion

Interstitial deletions of 1q23.3q24.1 are rare. Here, chromosomal microarray testing identified a de novo microdeletion of arr[GRCh37]1q23.3q24.1(164816055_165696996) × 1 in a patient with moderate developmental delay, hearing loss, cryptorchidism, and other distinctive features. The clinical features were common to those previously reported in patients with overlapping deletions. The patient’s deletion size was 881 kb—the smallest yet reported. This therefore narrowed down the deletion responsible for the common clinical features. The deleted region included seven genes; deletion of LMX1A, RXRG, and ALDH9A1 may have caused our patient’s neurodevelopmental delay.

Rescue of Sly Expression Is Not Sufficient to Rescue Spermiogenic Phenotype of Mice with Deletions of Y Chromosome Long Arm

Mice with deletions of the Y-specific (non-PAR) region of the mouse Y chromosome long arm (NPYq) have sperm defects and fertility problems that increase proportionally to deletion size. Mice with abrogated function of NPYq-encoded gene Sly (sh367 Sly-KD) display a phenotype similar to that of NPYq deletion mutants but less severe. The milder phenotype can be due to insufficient Sly knockdown, involvement of another NPYq gene, or both. To address this question and to further elucidate the role of Sly in the infertile phenotype of mice with NPYq deletions, we developed an anti-SLY antibody specifically recognizing SLY1 and SLY2 protein isoforms and used it to characterize SLY expression in NPYq- and Sly-deficient mice. We also carried out transgene rescue by adding Sly1/2 transgenes to mice with NPYq deletions. We demonstrated that SLY1/2 expression in mutant mice decreased proportionally to deletion size, with ~12% of SLY1/2 retained in shSLY sh367 testes. The addition of Sly1/2 transgenes to mice with NPYq deletions rescued SLY1/2 expression but did not ameliorate fertility and testicular/spermiogenic defects. Together, the data suggest that Sly deficiency is not the sole underlying cause of the infertile phenotype of mice with NPYq deletions and imply the involvement of another NPYq gene.