C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome.

Nabais Sa-de Vries syndrome (NSDVS) is an autosomal dominant neurodevelopmental disorder first described in 2020 and is classified into type 1 (NSDVS1) and type 2 (NSDVS2) which encompassed of spectrum of distinct clinical features due to gain-of-function (GOF) and loss-of-function (LOF) variants respectively. So far only 6 cases of 5 different missense pathogenic variants had been reported which impact on the SPOP substrate binding affinity for the downstream ubiquitylation. Here, we report a novel and de novo heterozygous nonsense pathogenic variant, p.Tyr353Term at the BACK domain in a patient with neurodevelopmental delay plus mixed phenotypes of NSDVS type 1 and 2 using trio exome analysis. The BACK domain is functionally critical for the SPOP higher-order oligomerization and is shown to increase substrate binding avidity with enhanced ubiquitylation efficiency in vitro. Experimentally, a missense variant p.Tyr353Glu is proven to attenuate the tandem SPOP oligomer formation and we envisage the current truncated variant at the same residue would attenuate the oligomerization process. This is the first report providing in vivo clue about the clinical significance of SPOP oligomerization in human neurodevelopmental disorders with new understanding on the expanding spectrum of NSDVS. We conclude the p.Tyr353Term is a Janus-faced variant which explains the dual NSDVS type 1 and 2 phenotypes in this case.

Beyond Sector Retinitis Pigmentosa: Expanding the Phenotype and Natural History of the Rhodopsin Gene Codon 106 Mutation (Gly-to-Arg) in Autosomal Dominant Retinitis Pigmentosa.

Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression.

Genetic dissection of heterosis of indica-japonica by introgression line, recombinant inbred line and their testcross populations.

The successful implementation of heterosis in rice has significantly enhanced rice productivity, but the genetic basis of heterosis in rice remains unclear. To understand the genetic basis of heterosis in rice, main-effect and epistatic quantitative trait loci (QTLs) associated with heterosis for grain yield-related traits in the four related rice mapping populations derived from Xiushui09 (XS09) (japonica) and IR2061 (indica), were dissected using single nucleotide polymorphism bin maps and replicated phenotyping experiments under two locations. Most mid-parent heterosis of testcross F1s (TCF1s) of XS09 background introgression lines (XSILs) with Peiai64S were significantly higher than those of TCF1s of recombinant inbred lines (RILs) with PA64S at two locations, suggesting that the effects of heterosis was influenced by the proportion of introgression of IR2061's genome into XS09 background. A total of 81 main-effect QTLs (M-QTLs) and 41 epistatic QTLs were identified for the phenotypic variations of four traits of RILs and XSILs, TCF1s and absolute mid-parent heterosis in two locations. Furthermore, overdominance and underdominance were detected to play predominant effects on most traits in this study, suggesting overdominance and underdominance as well as epistasis are the main genetic bases of heterosis in rice. Some M-QTLs exhibiting positive overdominance effects such as qPN1.2, qPN1.5 and qPN4.3 for increased panicle number per plant, qGYP9 and qGYP12.1 for increased grain yield per plant, and qTGW3.4 and qTGW8.2 for enhanced 1000-grain weight would be highly valuable for breeding to enhance grain yield of hybrid rice by marker-assisted selection.

Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3.

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant is exclusively responsible for all cases of NR2E3-associated adRP. Currently, there is no treatment for NR2E3-related or, other, adRP, but genome editing holds promise. A pertinent approach would be to specifically knockout the dominant mutant allele, so that the wild type allele can perform unhindered. In this study, we developed a CRISPR/Cas strategy to specifically knockout the mutant G56R allele of NR2E3 and performed a proof-of-concept study in induced pluripotent stem cells (iPSCs) of an adRP patient. We demonstrate allele-specific knockout of the mutant G56R allele in the absence of off-target events. Furthermore, we validated this knockout strategy in an exogenous overexpression system. Accordingly, the mutant G56R-CRISPR protein was truncated and mis-localized to the cytosol in contrast to the (peri)nuclear localizations of wild type or G56R NR2E3 proteins. Finally, we show, for the first time, that G56R iPSCs, as well as G56R-CRISPR iPSCs, can differentiate into NR2E3-expressing retinal organoids. Overall, we demonstrate that G56R allele-specific knockout by CRISPR/Cas could be a clinically relevant approach to treat NR2E3-associated adRP.

A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect.

Cone dystrophies are a rare subgroup of inherited retinal dystrophies and hallmarked by color vision defects, low or decreasing visual acuity and central vision loss, nystagmus and photophobia. Applying genome-wide linkage analysis and array comparative genome hybridization, we identified a locus for autosomal dominant cone dystrophy on chromosome 16q12 in four independent multigeneration families. The locus is defined by duplications of variable size with a smallest region of overlap of 608 kb affecting the IRXB gene cluster and encompasses the genes IRX5 and IRX6. IRX5 and IRX6 belong to the Iroquois (Iro) protein family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissue in vertebrates, including the eye and the retina. All patients presented with a unique progressive cone dystrophy phenotype hallmarked by early tritanopic color vision defects. We propose that the disease underlies a misregulation of the IRXB gene cluster on chromosome 16q12 and demonstrate that overexpression of Irx5a and Irx6a, the two orthologous genes in zebrafish, results in visual impairment in 5-day-old zebrafish larvae.

A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family.

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype-phenotype correlations of DFNA68 hearing loss.

Quantifying the contribution of dominance deviation effects to complex trait variation in biobank-scale data.

The proportion of variation in complex traits that can be attributed to non-additive genetic effects has been a topic of intense debate. The availability of biobank-scale datasets of genotype and trait data from unrelated individuals opens up the possibility of obtaining precise estimates of the contribution of non-additive genetic effects. We present an efficient method to estimate the variation in a complex trait that can be attributed to additive (additive heritability) and dominance deviation (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. Over a wide range of genetic architectures, our method yields unbiased estimates of additive and dominance heritability. We applied our method, in turn, to array genotypes as well as imputed genotypes (at common SNPs with minor allele frequency [MAF] > 1%) and 50 quantitative traits measured in 291,273 unrelated white British individuals in the UK Biobank. Averaged across these 50 traits, we find that additive heritability on array SNPs is 21.86% while dominance heritability is 0.13% (about 0.48% of the additive heritability) with qualitatively similar results for imputed genotypes. We find no statistically significant evidence for dominance heritability (p<0.05/50 accounting for the number of traits tested) and estimate that dominance heritability is unlikely to exceed 1% for the traits analyzed. Our analyses indicate a limited contribution of dominance heritability to complex trait variation.

A rare disorder causing chronic joint pain in an adolescent.

ABSTRACT: This article describes a patient with chronic knee pain and deformities of her hands and feet that led to a diagnosis of nail-patella syndrome, a rare autosomal dominant disorder.

Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance.

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis.

The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death. Mutations in the gene DNAJC5 that codes for the presynaptic co-chaperone cysteine string protein-α (CSPα) were recently reported in sporadic adult-onset cases and in families with dominant inheritance. The mutant CSPα protein may lead to disease progression by both loss and gain of function mechanisms. Iron chelation therapy may be considered as a possible pharmaceutical intervention based on our recent mechanism-based proposal of CSPα oligomerization via ectopic Fe-S cluster-binding, summarized in this review.

Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.

Dominant SCN2A mutation with variable phenotype in two generations.

BACKGROUND: SCN2A mutations are some of the commonest causes of neurodevelopmental disorders including epilepsy, movement disorders, autism spectrum disorder, intellectual disability and rarely episodic ataxia. CASE REPORT: We present a patient with a dominantly inherited SCN2A mutation presenting as episodic ataxia in a boy and episodic hemiplegia in his father. We have briefly reviewed the literature of SCN2A mutations presenting with episodic ataxia. CONCLUSION: Our report has expanded the phenotype for SCN2A mutations.

A case of severe autosomal dominant spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 mutation.

BACKGROUND: Heterozygous variants in BICD2 cause autosomal dominant spinal muscular atrophy with lower extremity predominance. These variants are also identified in individuals with severe forms of congenital muscle atrophy representing arthrogryposis multiplex. CASE REPORT: A girl was born with severe muscle weakness and respiratory distress. A fetal ultrasound had detected polyhydramnios and multiple joint contractures in utero. She was born with severe muscle weakness and respiratory distress. Bilateral hip joint dislocation and multiple bone fractures were also present at birth. Although she depends on medical care, including assisted ventilation and tube feeding, she has reached eight years of age. Her motor developmental skills were reduced owing to muscle weakness and deformity of her lower extremities, whereas her cognitive development slowly but steadily grew. Whole exome sequencing revealed a novel de novo missense BICD2 variant (c.1625G > A, p.(Cys542Tyr)), which was evaluated as likely pathogenic. CONCLUSION: This is the first case report of a severe form of spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 variant in Japan.

Craniofacial phenotypes associated with Robinow syndrome.

Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients. Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes.

INTRODUCTION: A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. METHODS: A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. RESULTS: Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. DISCUSSION: Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.

Lethal mutations with fluctuating heterozygous effect: the lethal force of effective dominance.

The theory of population genetics leads to the expectation that in very large populations the frequencies of recessive lethal mutations are close to the square root of the mutation rate, corresponding to mutation-selection balance. There are numerous examples where the frequencies of such alleles are orders of magnitude larger than this result. In this work we theoretically investigate the role of temporal fluctuations in the heterozygous effect (h) for lethal mutations in very large populations. For fluctuations of h, around a mean value of [Formula: see text], we find a biased outcome that is described by an effective dominance coefficient, heff, that is generally less than the mean dominance coefficient, i.e., [Formula: see text]. In the case where the mean dominance coefficient is zero, the effective dominance coefficient is negative: heff < 0, corresponding to the lethal allele behaving as though overdominant and having an elevated mean frequency. This case plausibly explains mean allele frequencies that are an order of magnitude larger than the equilibrium frequency of a recessive allele with a constant dominance coefficient. Our analysis may be relevant to explaining lethal disorders with anomalously high frequencies, such as cystic fibrosis and Tay-Sachs, and may open the door to further investigations into the statistics of fluctuations of the heterozygous effect.

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci.

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

Collagen I and collagen III polymorphisms in women with pelvic organ prolapse.

AIMS: Verify the presence of the single nucleotide polymorphisms rs1800012 of the collagen I (COL1A1) and rs1800255 of the collagen III (COL3A1) genes and their association with pelvic organ prolapse (POP) in Brazilian women and to determine risk factors for POP. METHODS: We assessed 826 postmenopausal women divided into POP (stages III and IV) and control groups (stages 0 and I) by examination and peripheral blood sample collection. DNA sequences of interest were analyzed by real-time reverse-transcriptase polymerase chain reaction. We used logistic regression analyses, recessive and codominance models of inheritance, and P < .05 for significance. RESULTS: Six-hundred and thirty-four postmenopausal women were included: 348 (54.8%) POP cases and 286 (45.1%) controls. The frequencies of GG, GA, and AA genotypes for COL1A1 were 69.12%, 20.24%, and 10.59% in POP group and 71.79%, 20%, and 8.21% in controls; GG, GT, and TT for COL3A1 were 37.54%, 59.53%, and 2.93% in POP group and 36.24%, 60.14%, and 3.62% in controls. There were no genotypic or allelic association with POP phenotype that link both SNPs rs1800012 and rs1800255 to increased risk of POP. Vaginal delivery (odds ratio [OR] = 13; 95% confidence interval [CI] [4.00-47.08]), POP family history (OR = 3.1; 95% CI [1.49-6.50]), diabetes mellitus (OR = 2.3; 95% CI [1.08-5.21]), number of pregnancies (OR = 1.2; 95% CI [1.05-1.36]), and age (OR = 1.1; 95% CI [1.09-1.19]), were variables of increased risk for POP (P < .05 for all). CONCLUSION: Our study suggests lack of association between DNA polymorphisms rs1800012 of COL1A1 and rs1800255 of COL3A1 with advanced POP. Vaginal delivery, POP family history, diabetes mellitus, number of pregnancies, and age are risk factors for POP.