Optimization of irrigation and fertilization of apples under magnetoelectric water irrigation in extremely arid areas.

Apple (Malus pumila Mill.) is one of the important economic crops in the arid areas of Xinjiang, China. For a long time, there has been a problem of high consumption but low yield in water and fertilizer management, prevent improvements in apple quality and yield. In this study, 5-year-old 'Royal Gala' apple trees in extremely arid areas of Xinjiang were used as experimental materials to carry out field experiments. considering 5 irrigation levels (W1, 30 mm; W2, 425 mm; W3, 550 mm; W4, 675 mm; W5, 800 mm) and 5 fertilization levels (F1, 280 kg·ha-1; F2, 360 kg·ha-1; F3, 440 kg·ha-1; F4, 520 kg·ha-1; F5, 600 kg·ha-1) under magnetoelectric water irrigation conditions. The results demonstrated that magnetoelectric water combined with the application of 675 mm irrigation amount and 520 kg·ha-1 fertilization amount was the most effective combination. These results occurred by increasing net photosynthetic rate of apple leaves, improved the quality of apples, increased apple yield, and promoted the improvement of water and fertilizer use efficiency. Additionally, the quadratic regression model was used to fit the response process of yield, IWUE and PFP to irrigation amount and fertilization amount, and the accuracy was greater than 0.8, indicating good fitting effects. The synergistic effect of water and fertilizer has a positive effect on optimizing apple water and fertilizer management. Principal component analysis showed that the magnetoelectric treatment combined water and fertilizer mainly affected apple yield, water and fertilizer use efficiency and vitamin C content related to quality. This study provides valuable guidance for improving water and fertilizer productivity, crop yield and quality in extreme arid areas of Xinjiang by using Magnetoelectric water irrigation.

Crop Leaf Phenotypic Parameter Measurement Based on the RKM-D Point Cloud Method.

Crop leaf length, perimeter, and area serve as vital phenotypic indicators of crop growth status, the measurement of which is important for crop monitoring and yield estimation. However, processing a leaf point cloud is often challenging due to cluttered, fluctuating, and uncertain points, which culminate in inaccurate measurements of leaf phenotypic parameters. To tackle this issue, the RKM-D point cloud method for measuring leaf phenotypic parameters is proposed, which is based on the fusion of improved Random Sample Consensus with a ground point removal (R) algorithm, the K-means clustering (K) algorithm, the Moving Least Squares (M) method, and the Euclidean distance (D) algorithm. Pepper leaves were obtained from three growth periods on the 14th, 28th, and 42nd days as experimental subjects, and a stereo camera was employed to capture point clouds. The experimental results reveal that the RKM-D point cloud method delivers high precision in measuring leaf phenotypic parameters. (i) For leaf length, the coefficient of determination (R2) surpasses 0.81, the mean absolute error (MAE) is less than 3.50 mm, the mean relative error (MRE) is less than 5.93%, and the root mean square error (RMSE) is less than 3.73 mm. (ii) For leaf perimeter, the R2 surpasses 0.82, the MAE is less than 7.30 mm, the MRE is less than 4.50%, and the RMSE is less than 8.37 mm. (iii) For leaf area, the R2 surpasses 0.97, the MAE is less than 64.66 mm2, the MRE is less than 4.96%, and the RMSE is less than 73.06 mm2. The results show that the proposed RKM-D point cloud method offers a robust solution for the precise measurement of crop leaf phenotypic parameters.

Application of carboxymethyl cellulose sodium (CMCNa) in maize-wheat cropping system (MWCS) in coastal saline-alkali soil.

Sodium carboxymethyl cellulose (CMCNa) application has been a promising approach to improve soil quality. The purpose of this study was to explore the effects of CMC-Na on soil infiltration, evaporation, water-salt distribution, crop growth, water use efficiency and net profit (Net) in a coastal saline-alkali soil maize-wheat cropping system (MWCS). Five CMC-Na application amounts (0, 0.1, 0.2, 0.4 and 0.6 g kg-1) were designed for the soil column experiment indoor, and five CMC-Na application amounts were used in 2019-2020 field experiment (CK: 0, C10: 10 kg ha-1, C20: 10 kg ha-1, C30: 10 kg ha-1 and C50: 10 kg ha-1), No treatment will be applied in 2021. The results showed that (1) CMC-Na treatment reduced soil cumulative infiltration, infiltration rate, daily evaporation, and cumulative evaporation. (2) After the application of CMCNa, the average soil water storage (SWS) in the 0-60 cm soil layer increased, and soil salinity (SSC) decreased in most treatments. (3) In the 2019-2020, the maize aboveground biomass (B), yield (Y) and water use efficiency (WUE) were the highest under the C20 and C30 treatments, which were 15.24 and 15.32 t ha-1, 5.67 and 5.49 t ha-1 and 1.74 and 1.52 kg ha-1 mm-1, respectively, and the wheat under C30 treatment is the highest, which were 10.98 t ha-1, 5.27 t ha-1 and 1.78 kg ha-1 mm-1. (4) A dose of 25.5 kg ha-1 and 38.9 kg ha-1 was recommended as the most optimal CMC-Na application for maize and wheat in coastal saline alkali soil, respectively.

Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.

GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease.

A case of familial frontotemporal dementia caused by a progranulin gene mutation.

After Alzheimer's disease, Frontotemporal dementia (FTD) is the most common cause of early-onset dementia. Several genetic mutations have been identified in familial FTD, with mutations in progranulin (GRN) accounting for approximately 20-25% of familial FTD cases and about 10% of total FTD cases. We report the case of a familial FTD patient with atypical parkinsonism who was found to have GRN frontotemporal dementia (GRN-FTD) with a pathogenic splice site mutation (c.709-2A > G) and notable phenotypic heterogeneity among family members.

The lived experience of reconstructing identity in response to genetic risk of frontotemporal degeneration and amyotrophic lateral sclerosis.

With the increasing availability of predictive genetic testing for adult-onset neurodegenerative conditions, it is imperative that we better understand the impact of learning one's risk status. Frontotemporal degeneration (FTD) is the second most prevalent cause of early-onset dementia. About one-third of patients have an identifiable genetic etiology, and some genetic variants that cause FTD can also cause amyotrophic lateral sclerosis (ALS). To understand individuals' risk perception and broader experience of living at risk, we completed semi-structured telephone interviews with 14 asymptomatic adults who tested positive for a variant known to cause risk for FTD and/or ALS. We conducted a thematic analysis, and within the core topic of identity, we derived three themes: conceptualization of FTD and ALS as a threat to identity, enduring uncertainty and dread, and varying centrality of risk status to identity. FTD and ALS risk raised fundamental issues for participants related to the essence of personhood, challenged them to confront Cartesian dualism (the philosophy of mind-body separation), and exposed how time, relationships, and social roles have affected their understanding of the nature of the self. Our findings provide important insight into how being at genetic risk shapes an individual's identity. We conclude that genetic counseling interventions that allow for identity exploration, anticipatory guidance, and uncertainty management should be utilized when supporting persons at risk.

Evaluation of an educational conference for persons affected by hereditary frontotemporal degeneration and amyotrophic lateral sclerosis.

Objective: There are limited studies exploring the support and education needs of individuals at-risk for or diagnosed with hereditary frontotemporal degeneration (FTD) and/or amyotrophic lateral sclerosis (ALS). This study evaluated a novel conference for this population to assess conference efficacy, probe how participants assessed relevant resources, and identify outstanding needs of persons at-risk/diagnosed. Methods: We implemented a post-conference electronic survey that probed participants' satisfaction, prior experience with resources, and unmet needs. Along with multiple-choice, free-text items were included to gather qualitative context. Results: Survey completion rate was 31% (115/376 attendees who were emailed the survey). There was positive interest in pursuing genetic counseling among eligible responders: 61% indicated they planned to seek genetic counseling because of the conference, which was significantly more than those who were undecided (21%) or did not plan to seek genetic counseling (18%). Qualitative data demonstrated need for additional education, support, and research opportunities. Conclusion: Conference reactions indicate this is a valued resource. Results indicated the importance of raising awareness about existing resources, and the need for further resource development, especially for at-risk communities. Innovation: While most resources are developed for caregivers' needs, this unique program targets at-risk individuals and unites ALS and FTD communities.

The Genetic Testing Experience of Individuals with Parkinson's Disease.

Background: The perspective and experiences of individuals with Parkinson's disease (PD) regarding genetic testing is limited. Objectives: To determine if anticipated benefits and negative consequences of genetic testing noted in prior studies have occurred in a surveyed group of patients with PD and to identify reasons why some individuals with PD have not had testing. Methods: Individuals were surveyed from 22 support/advocacy groups throughout the US. Information about patient demographics and genetic testing were assessed, along with the consequences experienced after testing or anticipated by those who have not had testing. Descriptive statistics, Pearson correlation coefficient, ANOVA, and independent sample t-test were utilized for data analysis. Results: Of the genetic testing group (n = 78), most received testing through a research study (44.9%) or a Direct-to-Consumer company (46.2%). Most did not meet with a genetic counselor before (87.2%) or after testing (64.1%). Fewer positive and fewer negative consequences were reported after testing compared to the consequences anticipated by those who have not undergone testing (P < 0.001, all comparisons). Of the non-genetic testing group (n = 166), 49.4% did not undergo testing because they were not aware it was available and 38.0% because their doctor did not offer it. Conclusions: Findings demonstrate the need for providers to have genetic testing discussions with PD patients, who may otherwise seek testing via Direct-to-Consumer companies or be unaware it is available. Collaborations with genetic counselors trained in providing anticipatory guidance may assist patients in forming more realistic expectations regarding the consequences experienced after genetic testing for PD.

Sex Chromosome Rearrangement Associated With Hormonal Abnormalities and Gender Dysphoria.

Although disorders arising from sex chromosome and sex steroid abnormalities are well characterized from the perspectives of endocrinology, dysmorphology, and reproductive health, relatively little is known about neuropsychiatric development, gender identity, incongruence, and dysphoria in the populations with these disorders. In this report, we describe the case of a 21-year-old gender nonbinary individual identified as male at birth who presented to an academic psychiatry consultation clinic because of life-long gender dysphoria. The patient was found to have a complex sex chromosomal rearrangement and associated hormonal abnormalities that may, at least in part, explain the patient's history. In addition to describing a novel genetic change, this case and the accompanying review of the existing literature highlight the need for an increased focus on the psychiatric perspective, and sex and gender issues in particular, among all patients with sex chromosome abnormalities and inborn errors of steroid metabolism.

Agreement between parent-proxy and child self-report in pediatric hypermobile Ehlers-Danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common disorder in children and adolescents that negatively impacts health-related quality of life (HRQOL). It can include chronic pain, fatigue, autonomic dysfunction, and mood problems. The objective of this study was to examine levels of agreement between children and parents in the setting of hEDS and HRQOL. Individuals with hEDS, ages 10-20 years, and their parents were recruited to complete a series of surveys. Instruments included pediatric quality of life generic and multidimensional fatigue scales, Functional Disability Index, Pain-Frequency-Severity-Duration scale, Brief Illness Perception Questionnaire, and Herth Hope Index. Agreement on each measure was evaluated using statistical calculations. Thirty-six parent-child dyads completed the surveys. There were no significant differences between the means of parent and child scores. There was moderate to strong agreement on all survey scores. However, the proportion of dyads with disagreement was relatively high for each individual score. Eighteen dyads disagreed on at least half of the surveys. Body mass index centile and child perception of cognitive fatigue most strongly predicted disagreement in total HRQOL score. Proxy-reporters for children and adolescents with hEDS may agree with their child on average. However, due to significant frequency of clinically important disagreement, information from both children and their parents should be sought whenever possible.

Pearls & Oy-sters: Deep Phenotyping of Abnormal Eye Movements Advances the Detection of Gerstmann-Sträussler-Scheinker Syndrome.

A 58-year-old previously healthy woman presents with 3 years of rapidly progressive ataxia, parkinsonism, dysautonomia, peripheral neuropathy, leg weakness, spasticity, hyperreflexia, and mild vertical-gaze palsy. She has a matrilineal family history of neurodegenerative diseases. She was initially postulated to have spinocerebellar ataxia or atypical parkinsonism with cerebellar features. However, on closer inspection, her abnormal extraocular eye movements suggested rare mimicking disorders such as prion disease as part of the differential diagnosis, requiring further evaluation. This case highlights how deep phenotyping can open new diagnostic considerations, inform additional workup, and yield the precise diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS).

Effect of Sodium Carboxymethyl Cellulose on Water and Salt Transport Characteristics of Saline-Alkali Soil in Xinjiang, China.

The scientific use of sodium carboxymethyl cellulose (CMC) to improve the production capacity of saline-alkali soil is critical to achieve green agriculture and sustainable land use. It serves as a foundation for the scientific use of CMC to clarify the water and salt transport characteristics of CMC-treated soil. In this study, a one-dimensional soil column infiltration experiment was carried out to investigate the effects of different CMC dosages (0, 0.2, 0.4, 0.6, and 0.8 g/kg) on the infiltration characteristics, infiltration model parameters, water and salt distribution, and salt leaching of saline-alkali soil in Xinjiang, China. The results showed that the final cumulative infiltration of CMC-treated soil increased by 8.63-20.72%, and the infiltration time to reach the preset wetting front depth increased by 1.02-3.96 times. The sorptivity (S) in the Philip infiltration model and comprehensive shape coefficient (α) in the algebraic infiltration model showed a trend of increasing first and then decreasing with CMC dosage, revealing a quadratic polynomial relationship. The algebraic model could accurately simulate the water content profile of CMC-treated soil. CMC enhanced the soil water holding capacity and salt leaching efficiency. The average soil water content, desalination rate, and leaching efficiency were increased by 5.18-15.54%, 21.17-57.15%, and 11.61-30.18%, respectively. The effect of water retention and salt inhibition on loamy sand was the best when the CMC dosage was 0.6 g/ kg. In conclusion, the results provide a theoretical basis for the rational application of CMC to improve saline-alkali soil in arid areas.

Experimental Investigation of the Different Polyacrylamide Dosages on Soil Water Movement under Brackish Water Infiltration.

The use of soil conditioners in conjunction with brackish water irrigation is critical for the efficient development and use of brackish water as well as the enhancement of the structure of saline soil and stimulating crop growth. This study investigated the effects of different polyacrylamide (PAM) dosages (0, 0.02%, 0.04%, and 0.06%) on the water flow properties of sandy loam during brackish water infiltration using one-dimensional vertical and horizontal soil column infiltration experiments. The results showed that: (1) PAM could lower the soil infiltration rate and increase soil water retention performance under brackish water infiltration conditions. (2) PAM had a significant effect on the parameters of the Philip and Kostiakov infiltration models. The soil sorption rate S and the empirical coefficient λ were the smallest, and the empirical index ß was the largest when the PAM dosage was 0.04%. (3) PAM dosage displayed a quadratic polynomial connection with the soil saturated water content and the saturated hydraulic conductivity. The soil saturated water content was highest when the PAM dosage was 0.04%, the intake suction hd of the Brooks-Corey model increased by 15.30%, and the soil water holding capacity was greatly improved. (4) Soil treated with PAM could absorb more water under the same soil water suction, whereas the soil unsaturated hydraulic conductivity and its growth rate decreased. The soil saturated diffusion rate Ds, as well as the soil water diffusion threshold, rose. Finally, the 0.04% PAM dosage could improve soil hydrodynamic characteristics under brackish water infiltration, which is beneficial for the efficient utilization of brackish water.

Magnetic Water Treatment: An Eco-Friendly Irrigation Alternative to Alleviate Salt Stress of Brackish Water in Seed Germination and Early Seedling Growth of Cotton (Gossypium hirsutum L.).

Magnetized water has been a promising approach to improve crop productivity but the conditions for its effectiveness remain contradictory and inconclusive. The objective of this research was to understand the influences of different magnetized water with varying quality on seed absorption, germination, and early growth of cotton. To this end, a series of experiments involving the seed soaking process, germination test, and pot experiment were carried out to study the effects of different qualities (fresh and brackish water) of magnetized water on seed water absorption, germination, seedling growth, photosynthetic characteristics, and biomass of cotton in 2018. The results showed that the maximum relative water absorption of magnetized fresh and magnetized brackish water relatively increased by 16.76% and 19.75%, respectively, and the magnetic effect time of brackish water was longer than fresh water. The relative promotion effect of magnetized brackish water on cotton seed germination and growth potential was greater than magnetized fresh water. The cotton seeds germination rate under magnetized fresh and magnetized brackish water irrigation relatively increased by 13.14% and 41.86%, respectively, and the relative promoting effect of magnetized brackish water on the vitality indexes and the morphological indexes of cotton seedlings was greater than magnetized fresh water. Unlike non-magnetized water, the net photosynthetic rate (Pn), transpiration rate (Tr), and instantaneous water use efficiency (iWUE) of cotton irrigated with magnetized water increased significantly, while the stomatal limit value (Ls) decreased. The influences of photosynthesis and water use efficiency of cotton under magnetized brackish water were greater than magnetized fresh water. Magnetized fresh water had no significant effect on biomass proportional distribution of cotton but magnetized brackish water irrigation markedly improved the root-to-stem ratio of cotton within a 35.72% range. Therefore, the magnetization of brackish water does improve the growth characteristics of cotton seedlings, and the biological effect of magnetized brackish water is more significant than that of fresh water. It is suggested that magnetized brackish water can be used to irrigate cotton seedlings when freshwater resources are insufficient.

Genetic testing for the epilepsies: A systematic review.

OBJECTIVE: Numerous genetic testing options for individuals with epilepsy have emerged over the past decade without clear guidelines regarding optimal testing strategies. We performed a systematic evidence review (SER) and conducted meta-analyses of the diagnostic yield of genetic tests commonly utilized for patients with epilepsy. We also assessed nonyield outcomes (NYOs) such as changes in treatment and/or management, prognostic information, recurrence risk determination, and genetic counseling. METHODS: We performed an SER, in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), using PubMed, Embase, CINAHL, and Cochrane Central through December of 2020. We included studies that utilized genome sequencing (GS), exome sequencing (ES), multigene panel (MGP), and/or genome-wide comparative genomic hybridization/chromosomal microarray (CGH/CMA) in cohorts (n ≥ 10) ascertained for epilepsy. Quality assessment was undertaken using ROBINS-I (Risk of Bias in Non-Randomized Studies of Interventions). We estimated diagnostic yields and 95% confidence intervals with random effects meta-analyses and narratively synthesized NYOs. RESULTS: From 5985 nonduplicated articles published through 2020, 154 met inclusion criteria and were included in meta-analyses of diagnostic yield; 43 of those were included in the NYO synthesis. The overall diagnostic yield across all test modalities was 17%, with the highest yield for GS (48%), followed by ES (24%), MGP (19%), and CGH/CMA (9%). The only phenotypic factors that were significantly associated with increased yield were (1) the presence of developmental and epileptic encephalopathy and/or (2) the presence of neurodevelopmental comorbidities. Studies reporting NYOs addressed clinical and personal utility of testing. SIGNIFICANCE: This comprehensive SER, focused specifically on the literature regarding patients with epilepsy, provides a comparative assessment of the yield of clinically available tests, which will help shape clinician decision-making and policy regarding insurance coverage for genetic testing. We highlight the need for prospective assessment of the clinical and personal utility of genetic testing for patients with epilepsy and for standardization in reporting patient characteristics.

Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form.

Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype-phenotype associations.

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.