Gene Variants Research Articles

Genetic analysis of a Chinese pedigree affected with Achromatopsia due to variants of CNGA3 gene and a literature review

To explore the molecular basis for a Chinese pedigree affected with Achromatopsia (ACHM). A pedigree with ACHM which was admitted to the Women and Children's Hospital of Ningbo University on April 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Related literature was reviewed, and clinical and genetic features of Chinese patients with ACHM due to variants of CNGA3 gene were summarized. WES revealed that the proband and his younger brother had both harbored compound heterozygous variants of the CNGA3 gene, namely c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69), which were respectively inherited from their mother and father. The c.1190G>T was a known pathogenic variant, whilst the c.2013del was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2013del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1_Moderate+PM3+PP4). Literature review has identified 41 CNGA3 gene variants among 43 patients from 38 pedigrees, most of which were missense variants and had located in exon 8. Most patients were males, with nystagmus, photophobia, amblyopia and other symptoms during infancy/childhood as the main clinical manifestations, and there was a lack of genotype-phenotype correlation. The c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69) variants of the GNGA3 gene probably underlay the ACHM in the proband. Discovery of the c.2013del variant has enriched the mutational spectrum of the GNGA3 gene and provided a basis for genetic counseling and reproduction guidance for this pedigree.

Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease

To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.

Genetic analysis of a child with pachygyria due to variant of ADGRG1 gen

To explore the genetic basis for a child with pachygyria. A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.

Genetic analysis of a child with Primary hypertrophic osteoarthropathy

To explore the genetic etiology of a child with Primary hypertrophic osteoarthropathy. A child who was admitted to Zhongnan Hospital of Wuhan University on July 27, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing. Suspected splicing variant was verified by Sanger sequencing of family members. In vitro function was validated through a minigene assay, whilst the suspected exonic deletion was validated by long-fragment PCR. Whole exome sequencing revealed that the child has harbored compound heterozygous variants of HPGD gene, including a heterozygous deletion (exon 3 del) derived from his father and a splicing variant (c.421+1G>T) derived from his mother. Long-fragment PCR verified that the child and his father had both harbored a 7 565 bp heterozygous deletion (c.218-1304_324+6156del), whilst the minigene assay proved that the splicing variant has resulted in skipping of exon 4. The heterozygous c.218-1304_324+6156del deletion and the c.421+1G>T splicing variant of the HPGD gene probably underlay the pathogenesis in this child. Above finding has enriched the mutational spectrum of the HPGD gene and provided a basis for genetic counseling and prenatal diagnosis for this family.

Genetic and clinical analysis of two children with microcephaly and mental retardation due to a frameshifting variant of CASK gene

To explore the clinical and genetic characteristics of two children with mental retardation and microcephaly. Two children who had visited the Anhui Children's Hospital respectively on March 12 and June 22, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from them and their parents, and subjected to chromosomal karyotyping and whole exome sequencing analyses. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. Chromosomal karyotyping and copy number detection of the two children had found no abnormality. Whole exome sequencing revealed that child 1 has harbored a c.471delT (p.Pro157Profs*9) frameshifting variant of the CASK gene, whilst child 2 has harbored a c.1259_1269delCTGAGAATAAC (p.Pro420fs*27) frameshifting variant of the CASK gene. Sanger sequencing confirmed that both variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants were rated as pathogenic (PVS1+PS2+PP3). The de novo variants of the CASK gene probably underlay the pathogenesis of mental retardation and microcephaly in both children.

Clinical phenotype and molecular genetic analysis of seven children with CHARGE syndrome

To explore the clinical phenotype and genetic etiology for seven children with CHARGE syndrome (CS). Clinical data of seven children with CS diagnosed between March 2020 and December 2022 at the Children's Hospital Affiliated to Zhengzhou University were analyzed. Genomic DNA was extracted from peripheral blood samples from the children and their parents, and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. The ages of the children had ranged from 1 day after birth to 12 years old, and all of them had shown growth retardation. The reasons for their admission had included postnatal breathing, swallowing and feeding difficulties in five cases. One child was found to have abnormal external genitalia in conjunct with hearing impairment, whilst another child had shown no secondary sexual characteristics during puberty. All of the children were found to harbor CHD7 gene variants, which included 3 nonsense variants, 2 frameshifting variants and 2 missense variants, i.e., c.6292C>T (p.R2098*), c.2754G>A (p.W918*), c.469C>T (p.R157*), c.3308T>A (p.V1103D), c.7111delC (p.Q2371Kfs), c.6023delA (p.D2008Vfs) and c.3565C>T (p.R1189C). All of the variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3308T>A (p.V1103D) and c.3565C>T (p.R1189C) variants were rated as likely pathogenic (PS2+PM2_Supporting+PP3), whilst the remainders were rated as pathogenic (PVS1+PS2+PM2_Supporting). There is strong clinical and genetic heterogeneity in CS. Early genetic testing may facilitate accurate diagnosis. The detection of novel variants has expanded the phenotypic spectrum of CS and the mutational spectrum of the CHD7 gene.

Colorectal cancer with a germline BRCA1 variant inherited paternally: a case report.

BRCA genes have well-known associations with breast and ovarian cancers. However, variations in the BRCA gene, especially germline variations, have also been reported in colorectal cancer (CRC). We present the case of a rectal cancer with a germline BRCA1 variation inherited from the paternal side. A 39-year-old male was admitted with rectal cancer. The patient underwent surgical resection and the pathologic diagnosis was adenocarcinoma. Next-generation sequencing was performed and a BRCA1 variant was detected. Reviewing the public database and considering the young age of the patient, the variant was suggested to be germline. The patient's father had had prostate cancer and next-generation sequencing testing revealed an identical BRCA1 variant. In the BRCA cancer group, there is relatively little attention paid to male cancers. The accumulation of male CRC cases linked to BRCA variations may help clarify the potential pathological relationship between the two.

Management of patients with reduced dihydropyrimidine dehydrogenase activity receiving combined 5-fluoruracil-/capecitabine-based chemoradiotherapy.

5‑Fluoruracil (5-FU) and its oral prodrug capecitabine are mainstays in combined chemoradiotherapy regimens. They are metabolized by dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants of the DPYD gene cause areduction in DPYD activity, leading to possibly severe toxicities. Therefore, patients receiving 5‑FU-/capecitabine-based chemoradiotherapy should be tested for DPYD variants. However, there are limited clinical data on treatment adjustments and tolerability in patients with decreased DPYP activity receiving combined chemoradiotherapy. Therefore, aretrospective analysis of the toxicity profiles of patients with decreased DPYD activity treated at our center was conducted. For all patients receiving 5‑FU-/capecitabine-based chemo(radio)therapy at our department, DPYD activity was routinely tested. Genotyping of four DPYD variants (DPYD*2A, DPYD*13, c.2846A > T, and haplotype B3) was conducted according to the recommendation of the German Society for Hematooncology (DGHO) using TaqMan hydrolysis polymerase chain reaction (PCR; QuantStudy3, Thermo FisherScientific, Darmstadt). DPYD variants and activity score as well as clinical data (tumor entity, treatment protocol, dose adjustments, and toxicity according to the Common Terminology Criteria for Adverse Events [CTCAE]) were assessed and reported. Of 261 tested patients, 21exhibited DPYD variants, 18of whom received chemoradiotherapy. All but one patient was treated for rectal or anal carcinoma. The observed rate of DPYD variants was 8.0%, and heterozygous haplotype B3 was the most common (5.75%). One patient exhibited ahomozygous DPYD variant. DPYD activity score was at least 0.5in heterozygous patients; chemotherapy dose was adjusted accordingly, with an applied dose of 50-75%. CTCAE grade2 skin toxicity (50%) and grade3 leukopenia (33.3%) were most common. One patient experienced atransient grade4 increase in transaminases. All high-grade toxicities were manageable with supportive treatment and transient. No CTCAE grade5 toxicities related to 5‑FU administration were observed. With dose reduction in heterozygous patients, toxicity was within the range of patients without DPYD variants. Our clinical data suggest that dose-adapted 5‑FU-/capecitabine-chemoradiotherapy regimens can be safely considered in patients with heterozygous clinically relevant DPYD variants, but that the optimal dosage still needs to be determined to avoid both increased toxicity and undertreatment in acurative setting.

Splice-altering variant of PJVK gene in a Mauritanian family with non-syndromic hearing impairment.

PJVK gene was recently shown to create hypervulnerability to sound in humans and was the first human gene implicated in non-syndromic hearing impairment due to neural defect. Targeted next-generation sequencing of over 150 known deafness genes was performed in the proband. Sanger sequencing was used to validate the PJVK variant and confirm familial segregation of the disease. A minigene-based assay has been performed to assess the impact of the variant on splicing. We identified a novel c.550-6A > G acceptor splice-site variant in the PJVK gene in the homozygous state in a Mauritanian child with severe to profound congenital deafness. The substitution was located in intron 4. The effect of the variation was demonstrated by a minigene assay which showed that the variation, an insertion of an additional 5 bp, created a new splice site resulting in the appearance of a premature stop codon (p.Phe184Tyrfs*26) and likely a truncated protein. This result constitutes a new splice-site variant report in the PJVK gene leading to DFNB59 type associated with autosomal recessive non-syndromic hearing impairment (ARNSHI).

A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC. The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family. We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models. We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein. Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.

HLA-DQB1 as a potential prognostic biomarker of hormonal therapy in patients with non-obstructive azoospermia

The gonadotropin treatment of infertile men may improve spermatogenesis and lead to sperm cell production, however, only a small fraction of treated patients positively responds to such therapy. To identify individual treatment prognostic biomarkers associated with responsiveness to gonadotropins, we compared the gene expression profiles of testicular oligobiopsies from 3 patients with non-obstructive azoospermia (NOA) who positively responded to therapy with a combination of human chorionic gonadotropin and recombinant follicle-stimulating hormone (hCG/rFSH) to those of 3 non-responders. We used Affymetrix Human Gene 1.0 ST microarrays. The results of the microarray evaluation were validated by the qPCR technique while gene variants of the HLA-DQB1 (major histocompatibility complex, class II, DQ beta 1) were subsequently sequenced. In our microarrays, we have identified most significantly 5 transcripts with different expression levels in responders versus non-responders groups. Our interest has been primarily focused on the transcript associated with the HLA-DQB1 gene. Because the expression of this gene was up-regulated in the non-responding patients and only patients with heterozygotic alleles of HLA-DQB1 turned out to be positive to gonadotropin therapy, we suggest that this gene may be a biomarker of potential significance for the gonadotropin treatment of male infertility. We also compared the testicular gene expression profile in one individual before and after gonadotropin treatment. In the re-biopsied sample, we have identified over 600 genes that showed differences in testicular expression; some of these genes are critical for spermiogenesis. Thus, we documented that the applied gonadotropins successfully stimulated the spermatogenetic wave in patients with NOA.

Nonamyloidogenic TTR gene variants c.76G>A and c.337-18G>C are not associated with idiopathic small-fiber neuropathy.

Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.

Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.

Aminoacyl-transfer RiboNucleic Acid synthetases (ARSs) are essential enzymes that catalyze the attachment of each amino acid to their cognate tRNAs. Mitochondrial ARSs (mtARSs), which ensure protein synthesis within the mitochondria, are encoded by nuclear genes and imported into the organelle after translation in the cytosol. The extensive use of next generation sequencing (NGS) has resulted in an increasing number of variants in mtARS genes being identified and associated with mitochondrial diseases. The similarities between yeast and human mitochondrial translation machineries make yeast a good model to quickly and efficiently evaluate the effect of variants in mtARS genes. Genetic screening of patients with a clinical suspicion of mitochondrial disorders through a customized gene panel of known disease-genes, including all genes encoding mtARSs, led to the identification of missense variants in WARS2, NARS2 and RARS2. Most of them were classified as Variant of Uncertain Significance. We exploited yeast models to assess the functional consequences of the variants found in these genes encoding mitochondrial tryptophanyl-tRNA, asparaginyl-tRNA, and arginyl-tRNA synthetases, respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate, Cox2 steady-state level and mitochondrial protein synthesis were analyzed in yeast strains deleted in MSW1, SLM5, and MSR1 (the yeast orthologues of WARS2, NARS2 and RARS2, respectively), and expressing the wild type or the mutant alleles. Pathogenicity was confirmed for most variants, leading to their reclassification as Likely Pathogenic. Moreover, the beneficial effects observed after asparagine and arginine supplementation in the growth medium suggest them as a potential therapeutic approach.

Familial thrombotic microangiopathy in a child with coenzyme Q10 deficiency-associated glomerulopathy.

We report a child with biallelic COQ6 variants presenting with familial thrombotic microangiopathy (TMA). A Chinese boy presented with steroid-resistant nephrotic syndrome at 8months old and went into kidney failure requiring peritoneal dialysis at 15months old. He presented with hypertensive encephalopathy with the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute on chronic kidney injury at 25months old following a viral illness. Kidney biopsy showed features of chronic TMA. He was managed with supportive therapy and plasma exchanges and maintained on eculizumab. However, he had another TMA relapse despite complement inhibition a year later. Eculizumab was withdrawn, and supportive therapies, including ubiquinol (50mg/kg/day) and vitamins, were optimized. He remained relapse-free since then for 4years. Of note, his elder sister succumbed to multiple organ failure with histological evidence of chronic TMA at the age of 4. Retrospective genetic analysis revealed the same compound heterozygous variants in the COQ6 gene.

Universal Genetic Testing for Newly Diagnosed Invasive Breast Cancer.

Between 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases. To evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer. This cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024. Of 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. In this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

A genetic investigation in five Chinese families with keratoconus

Background This study investigated the genetic characteristics of five Chinese families with keratoconus (KC). Methods In the five families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. Results The Pentacam tomographic composite index in those affected first-degree family members of the probands showed a pathological change. Five new variants were detected in the five probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 (HOMER3) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor (IGF1R) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 (EML6) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B (DOP1B) gene; and a heterozygous splice-site variant c.7776+2T>A in the neurobeachin-like protein 2 (NBEAL2) gene. These variations were predicted to be potentially pathogenic and associated with KC. Conclusion Five novel variants in HOMER3, IGF1R, EML6, DOP1B, and NBEAL2 genes were identified in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The findings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.

Progress towards understanding risk factor mechanisms in the development of autism spectrum disorders.

Autism spectrum disorders (ASD) are a heterogenous set of syndromes characterised by social impairment and cognitive symptoms. Currently, there are limited treatment options available to help people with ASD manage their symptoms. Understanding the biological mechanisms that result in ASD diagnosis and symptomatology is an essential step in developing new interventional strategies. Human genetic studies have identified common gene variants of small effect and rare risk genes and copy number variants (CNVs) that substantially increase the risk of developing ASD. Reverse translational studies using rodent models based on these genetic variants provide new insight into the biological basis of ASD. Here we review recent findings from three ASD associated CNV mouse models (16p11.2, 2p16.3 and 22q11.2 deletion) that show behavioural and cognitive phenotypes relevant to ASD. These models have identified disturbed excitation-inhibition neurotransmitter balance, evidenced by dysfunctional glutamate and GABA signalling, as a key aetiological mechanism. These models also provide emerging evidence for serotoninergic neurotransmitter system dysfunction, although more work is needed to clarify the nature of this. At the brain network level, prefrontal cortex (PFC) dysfunctional connectivity is also evident across these models, supporting disturbed PFC function as a key nexus in ASD aetiology. Overall, published data highlight the utility and valuable insight gained into ASD aetiology from preclinical CNV mouse models. These have identified key aetiological mechanisms that represent putative novel therapeutic targets for the treatment of ASD symptoms, making them useful translational models for future drug discovery, development and validation.

T2-relaxometry in a large cohort of hereditary transthyretin amyloidosis with polyneuropathy

Background Previously, T2-relaxation time (T2app) and proton spin density (ρ) detected nerve injury in a small group of ATTRv amyloidosis. Here, we aim to quantify peripheral nerve impairment in a large cohort of symptomatic and asymptomatic ATTRv amyloidosis and correlate T2-relaxometry markers with clinical parameters and nerve conduction studies (NCS). Methods Eighty participants with pathologic variants of the transthyretin gene (TTRv) and 40 controls prospectively underwent magnetic resonance neurography. T2-relaxometry was performed, allowing to calculate tibial ρ, T2app and cross-sectional-area (CSA). Detailed clinical examinations and NCS of tibial and peroneal nerves were performed. Results Forty participants were classified as asymptomatic TTRv-carriers, 40 as symptomatic patients with polyneuropathy. ρ, T2app and CSA were significantly higher in symptomatic ATTRv amyloidosis (484.2 ± 14.8 a.u.; 70.6 ± 1.8 ms; 25.7 ± 0.9 mm2) versus TTRv-carriers (413.1 ± 9.4 a.u., p < 0.0001; 62.3 ± 1.3 ms, p = 0.0002; 19.0 ± 0.8 mm2, p < 0.0001) and versus controls (362.6 ± 7.5 a.u., p < 0.0001; 59.5 ± 1.0 ms, p < 0.0001; 15.4 ± 0.5 mm2, p < 0.0001). Only ρ and CSA differentiated TTRv-carriers from controls. ρ and CSA correlated with NCS in TTRv-carriers, while T2app correlated with NCS in symptomatic ATTRv amyloidosis. Both ρ and T2app correlated with clinical score. Conclusion ρ and CSA can detect early nerve injury and correlate with electrophysiology in asymptomatic TTRv-carriers. T2app increases only in symptomatic ATTRv amyloidosis in whom it correlates with clinical scores and electrophysiology. Our results suggest that T2-relaxometry can provide biomarkers for disease- and therapy-monitoring in the future.

The Risk of Diabetes Associated with DDE Exposure and its Interaction with a Common FTO Gene Variant: The Pro-Saude Study, Brazil

The Risk of Diabetes Associated with DDE Exposure and its Interaction with a Common FTO Gene Variant: The Pro-Saude Study, Brazil

Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants

PurposeIdentifying pathogenic non-coding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic non-coding ‘second hits’ in trans with these is unknown. MethodsIn 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare non-coding variants on the other haplotype in introns, untranslated regions (UTRs), promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit, and performed functional testing where possible. ResultsWe identified 3,761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2,430 probands. For 1,366 (36.3%) of these, we identified at least one rare non-coding variant in trans. Bioinformatic filtering and clinical review, revealed seven to be a good clinical fit. After detailed characterisation, we identified likely diagnoses for three probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further three (PAH, LAMA2, IGHMBP2). ConclusionWe developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/non-coding variants and conclude that this mechanism is likely to be a rare cause of DDs.