MEIS2 (15q14) gene deletions in siblings with mild developmental phenotypes and bifid uvula: documentation of mosaicism in an unaffected parent

MEIS2 (Meis homeobox 2) encodes a homeobox protein in the three amino acid loop extension (TALE) family of highly conserved homeodomain-containing transcription regulators important for development. MEIS2 deletions/mutations have been associated with cleft lip/palate, dysmorphic facial features, cardiac defects, as well as intellectual disability at a variable severity. Here we report on one familial case that two affected siblings carry the same non-mosaic ~ 423 kb genomic deletion at 15q14 encompassing the entirety of CDIN1 and the last three exons (ex. 10, 11, 12) of the MEIS2 gene, while their unaffected father is mosaic for the same deletion in about 10% lymphocytes. Both siblings presented with mild developmental delay and bifid uvula, while no congenital cardiac abnormalities were identified. The elder sister also showed syncopal episodes and mild speech delay and the father had atrial septal defects. This is the first report showing multiple family members inherit a genomic deletion resulting in a MEIS2 partial truncation from a mosaic parent. Taken all together, this study has important implications for genetic counseling regarding recurrence risk and also points to the importance of offering MEIS2 gene tests covering both point mutations and microdeletions to individuals with milder bifid uvula and developmental delay.

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

Background/Aims: To elucidate the genetic causes of severe primary insulin-like growth factor-I deficiency (SPIGFD) by systematic, targeted, next-generation sequencing (NGS)-based resequencing of growth-related genes. Methods: Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. Results: We identified disease-causing, heterozygous, de novo variants in HRAS (p.Gly13Cys) and FAM111A (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous GHR nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the IGF2 gene (p.Arg156Cys) of a maternally imprinted gene in a less severely affected father and his affected daughter. We detected 2 other novel missense variants in SH2B1 and SOCS2, both were inherited from an unaffected parent. Conclusions: Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in HRAS, FAM111A, and GHR. Considering the increased risk of subjects with HRAS mutations for neoplasms, close clinical monitoring and a thorough discussion of the risk/benefit ratio of the treatment with recombinant IGF-I is mandatory. Segregation analysis proved to be critical in the interpretation of potential SPIGFD-associated gene variations.

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

Peripartum depression in parents with multiple sclerosis and psychiatric disorders in children

Background: Although many individuals with multiple sclerosis (MS) experience depression, there are no studies on the frequency and effect of peripartum depression among parents with MS. Objective: To examine the frequency of peripartum depression in individuals with MS and its potential association with children’s psychiatric disorders. Methods: We conducted a cohort study in British Columbia, Canada, using linked health databases, of parents with MS and their children, and age-matched unaffected parent–child dyads. The diagnosis of peripartum depression, MS and psychiatric disorders in children was based on information from hospital admission, physician visit and drug prescription claims. Results: Peripartum depression was significantly more common among MS parents ( n = 360) versus unaffected ( n = 1207) parents (25.8% vs 18.5%, p value 0.02), especially among MS affected fathers versus unaffected fathers (25.7% vs 10.2%, p value < 0.001). The incidence of psychiatric disorders in children was 3.3 and 2.7 per 100 child-years among children with and without an MS parent, respectively. The rate of psychiatric disorders was significantly higher in children with an MS parent (vs without, hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.03–1.74) and among children with parents who had peripartum depression (HR: 1.87; 95% CI: 1.36–2.55). Conclusion: Parental MS is associated with a higher risk of peripartum depression and increases the risk of psychiatric disorders in children.

Friction Stir Welding of AA2024-T3 plate – the influence of different pin types

Some aluminium alloys are difficult to join using traditional fusion (melting and solidification) welding techniques. Friction Stir Welding (FSW) is a solid-state welding technique that can join two plates of material without melting the workpiece material. This proecess uses a rotating tool to create the joint and it can be applied to alumium alloys in particular. Macrostructure, microstructure and micro hardness of friction stir welded AA2024-T3 joints were studied. The influence of tool pin profile on the microstructure and hardness of these joints was examined. Square, triflute and tapered cylinder pins were used and results from each weldment are reported. Vickers micro hardness tests and grain size measurements were taken from the transverse plane of welded samples. Distinct zones in the macrostructure were evident. The zones were identified by transitions in the microstructure and hardness of weld samples. The zones identified across the sample were the the unaffected parent metal, the Heat Affected Zone (HAZ), the Thermo-Mechanicaly Affected Zone (TMAZ), and the Nugget Zone (NZ). Measured hardness values varied through each FSW zone. The hardness in each zone was below that of the parent material. The HAZ had the lowest hardness across the weld profile for each pin type tested. The cylindrical pin consistently produced tunnel and joint-line defects. Pin profiles with flat surface features and/or flutes produced consolidated joints with no defects.