MNS1 (meiosis-specific nuclear structural protein-1 gene) encodes a structural protein implicated in motile ciliary function and sperm flagella assembly. To date, two different homozygous MNS1 variants have been associated with autosomal recessive visceral heterotaxy (MIM#618948). A French individual was identified with compound heterozygous variants in the MNS1 gene. A collaborative call was proposed via GeneMatcher to describe new cases with this rare syndrome, leading to the identification of another family. The first patient was a female presenting complete situs inversus and unusual symptoms, including severe myopia and dental agenesis of 10 permanent teeth. She was found to carry compound heterozygous frameshift and nonsense variants in MNS1. The second and third patients were sibling fetuses with homozygous in-frame deletion variants in MNS1 and homozygous missense variants in GLDN. Autopsies revealed a complex prenatal malformation syndrome. We add here new cases with the ultra-rare MNS1-related disorder and provide a review of all published individuals.

BACKGROUND: Parkinson\'s disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce.
METHODS: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated.
RESULTS: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs.
CONCLUSIONS: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10-7) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10-8). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.

BACKGROUND: Loss-of-function variants in MME (membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant, MME c.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. MME c.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic MME variant (c.467del; p.Pro156Leufs*14) in Family 2.
OBJECTIVE: We aimed to determine the pathogenicity of the MME c.1188+428A>G variant through segregation and splicing analysis.
METHODS: The splicing impact of the deep intronic MME variant c.1188+428A>G was assessed using an in vitro exon-trapping assay.
RESULTS: The exon-trapping assay demonstrated that the MME c.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon between MME exons 12 and 13. The incorporation of the pseudoexon into MME transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in MME exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of MME transcript leading to a pathogenic loss-of-function.
CONCLUSIONS: To our knowledge, this is the first report of a pathogenic deep intronic MME variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.

暂无摘要。

OBJECTIVE: To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.
METHODS: Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy. Targeted sequence capture array technique was used to screen potential pathologic variants. Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.
RESULTS: Fundus examination showed round macular lesions appeared in both eyes. Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye, but it was uneven and slightly elevated in the right eye. Fundus autofluorescence showed patchy hyper-autofluorescence in the macula. Visual field examination indicates central defects in both eyes. Electroretinogram (ERG) and multifocal ERG showed no obvious abnormalities. Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye. We found that the proband carried a missense variant (c.1972C>T) and a deletion variant (c.4717_4718del) of RP1L1, which were originated from the parents and formed compound heterozygous variants. Both variants are likely pathogenic according to the ACMG criteria. Multimodal imaging, ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.
CONCLUSIONS: A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family, which expands the understanding of phenotype and genotype in RP1L1 maculopathy.

A novel and distinct mutant with a phenotype, aeroplane wing (ae) is reported for the first time in the urban malaria vector Anopheles stephensi. The main aim of this study was to establish the mode of inheritance of the ae gene performing genetic crossings between the mutants and wild types. These mutants show extended open wings that are visible to naked eyes in both the sexes. Mutants were first noticed in a nutritionally stressed isofemale colony. Strategic genetic crosses revealed that the ae gene is a recessive, autosomal, and monogenic trait having full penetrance with uniform expression in its adult stage. Egg morphometric analysis confirmed that these mutants were intermediate variant. No significant differences were observed in the wing venation and size of ae mutants compared to their control parental lines. Further cytogenetic analysis on the ovarian polytene chromosome of ae mutant showed an inversion (3Li) on the 3L arm like its parental line. This ae mutant would be a prominent marker and could be useful to study the functions of related specific genes within its genome.

OBJECTIVE: Genetic variants contribute to differences in disease susceptibility. The aim of the study was to elucidate if variants can affect human disease inheritance.
METHODS: Recently, a list of germline hotspot genetic variants across human autosomal chromosomes was published. Recording the genetic variant hotspots across autosomal chromosomes, their frequency was calculated for each distinct type of genetic variant hotspot and for each autosomal chromosome. Then, OMIM autosomal dominant (AD) and recessive diseases (AR) were counted across each chromosome having maximum and minimum coverage of each type of genetic variant hotspot and the data were compared. Subsequently, the study focused on chromosome 16 with the maximum and chromosome 13 with the minimum number of SNP hotspots. AD and AR diseases were recorded, inside or near the reported SNP variant hotspots of chromosome 16 and 13, and the data were compared. The SPSS software was used for statistical analyses.
RESULTS: Autosomal dominant diseases were mainly found in low SNP hotspot chromosomal regions compared to recessive ones, underlying SNPs\' possible regulatory role in allelic imbalance. The haplotypic background may be the key factor for variant classification, which could explain the current inconsistencies among scientists with the same genetic variant to be classified as pathogenic, likely pathogenic, or of unknown significance.
CONCLUSIONS: Which came first: the SNPs or the type of inheritance? Third next-generation sequencing with long reads could answer by phasing SNP alleles\' haplotypes and tracing their in-cis and in-trans modulator function in human Mendelian and Complex inheritance.

Rice yellow mottle virus (RYMV) causes one of the most devastating rice diseases in Africa. Management of RYMV is challenging. Genetic resistance provides the most effective and environment-friendly control. The recessive resistance locus rymv2 (OsCPR5.1) had been identified in African rice (Oryza glaberrima), however, introgression into Oryza sativa ssp. japonica and indica remains challenging due to crossing barriers. Here, we evaluated whether CRISPR/Cas9 genome editing of the two rice nucleoporin paralogs OsCPR5.1 (RYMV2) and OsCPR5.2 can be used to introduce RYMV resistance into the japonica variety Kitaake. Both paralogs had been shown to complement the defects of the Arabidopsis atcpr5 mutant, indicating partial redundancy. Despite striking sequence and structural similarities between the two paralogs, only oscpr5.1 loss-of-function mutants were fully resistant, while loss-of-function oscpr5.2 mutants remained susceptible, intimating that OsCPR5.1 plays a specific role in RYMV susceptibility. Notably, edited lines with short in-frame deletions or replacements in the N-terminal domain (predicted to be unstructured) of OsCPR5.1 were hypersusceptible to RYMV. In contrast to mutations in the single Arabidopsis AtCPR5 gene, which caused severely dwarfed plants, oscpr5.1 and oscpr5.2 single and double knockout mutants showed neither substantial growth defects nor symptoms indicative lesion mimic phenotypes, possibly reflecting functional differentiation. The specific editing of OsCPR5.1, while maintaining OsCPR5.2 activity, provides a promising strategy for generating RYMV-resistance in elite Oryza sativa lines as well as for effective stacking with other RYMV resistance genes or other traits.

FLNC gene encodes for Filamin-C (FLNC) protein, a sacromeric protein with important structural and signaling functions in the myocyte. Pathogenic dominant variants in FLNC were initially linked to myofibrillar myopathy and over time, evidence showed association of this gene with different forms of autosomal dominant cardiomyopathy including hypertrophic, dilated and restrictive forms. Recently, two cases of recessive FLNC mutations have been reported by Reinstein et al. and Kölbel et al., one with only cardiomyopathy and other with only myopathy. In this report, we describe a third case, a boy who was diagnosed at 10 years of age with shortness of breath and dilated cardiomyopathy who on sequencing was found to have a novel homozygous splice site variant (NM_001458.4 c.2122-1G>C) in FLNC. This case suggests that the phenotype associated with variants in FLNC is very heterogenous and can be inherited in dominant or recessive forms, with later being more severe and of earlier onset.