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Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspond to specific modes of inheritance and correlate clinical phenotypes has not been comprehensively explored. In this systematic review, we assess current case reports and series that describe patients with JPH2 variants and cardiac disease. We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD. In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease.

An 11-month-old boy with productive cough was referred to our hospital. He had nasal obstruction immediately after birth, and wheezing, wet cough, and rhinorrhea were observed daily after the neonatal period. Clinical and imaging findings revealed secretory otitis media, chronic sinusitis, and bronchiectasis. Primary ciliary dyskinesia was suspected. Transmission electron microscopy of nasal cilia showed defects of the outer and inner dynein arms. Genetic examinations of the family revealed copy number variation in PIH1 domain-containing 3 (PIH1D3) in the proband and mother. This is the first report of a Japanese patient with primary ciliary dyskinesia caused by copy number variation in PIH1D3.

PURPOSE To demonstrate phenotypic discordance between a monozygotic twin pair, one of whom exhibited pigmented paravenous chorioretinal atrophy (PPCRA). METHODS A patient and his identical twin brother, attending Moorfields Eye Hospital, were reviewed. Clinical assessment included visual acuity and color vision testing, fundus imaging including autofluorescence, spectral-domain optical coherence tomography and static perimetry. In addition, the affected sibling underwent pattern and full field electroretinography (PERG and ERG) according to ISCEV standards. Zygosity testing was performed using short tandem repeat (STR) analysis. RESULTS The 48-year old proband was referred with abnormal visual fields and difficulty reading at near. Examination revealed 20/20 Snellen visual acuity bilaterally, normal colour vision and bilateral asymmetric outer retinal atrophy with intra-retinal pigment migration along the course of the retinal veins, consistent with PPCRA. The visual field defects were contiguous with the blind spot and mirrored the retinal involvement in both eyes. Pattern ERG showed mild macular dysfunction and full field ERG was within normal limits. Blood testing for common uveitic entities was non-contributory. The proband's twin brother's clinical assessment and retinal imaging showed no abnormality. Zygosity testing showed the twins to be identical for 24 short tandem repeat (STR) microsatellite markers, indicative of monozygosity. CONCLUSION Some cases of PPCRA, without an obvious inflammatory etiology, do not have a clear Mendelian inheritance pattern and may represent an acquired disorder.

BACKGROUND Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison's disease, AD). Affected persons present a significant co-occurrence of autoimmune conditions, hence, clustering of autoimmunity is also predicted among their relatives. AIMS The aim of our study was to evaluate the burden of autoimmunity in families of people with AD. METHODS 116 individuals with AD were surveyed about the occurrence of 23 autoimmune diseases among their relatives. RESULTS 74.1% of persons with AD reported at least one relative with an autoimmune disorder - 257 cases were diagnosed in 221 relatives. Hashimoto's thyroiditis was found in 100 individuals, followed by Graves' disease and vitiligo - in 25 and 24 relatives, respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, while premature menopause in 8 women. AD was found in 7 relatives, alopecia in 6, and celiac disease in 5. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (p = 0.031). 66.4% of people with AD had a first-degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (p

A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

Spastic paraplegia (SPG) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations. Despite of the new molecular technologies, many patients remain yet undiagnosed. The purpose of this study was to describe the clinical presentation and molecular characteristics of a cohort of 27 patients from 18 different families with SPG in the south of Spain. We used a targeted next-generation sequencing (NGS) approach to study a proband from each family. Variants in SPG11 gene were the most common cause of SPG in our area. We made a genetic diagnosis in 52% of cases, identified 3 novel variants and reclassified one uncertain variant in SPG11 gene as pathogenic variant. We identified a patient with two truncanting mutation in SPG11 gene and late onset disease and report another missense mutation outside of motor domain of KIF1A gene in a family with pure SPG. Our study contributes to enhance the scientific knowledge of SPG. It is important to note the large group of cases (48%) that were not genetically diagnosed in our cohort. Therefore NGS approach is an efficient diagnostic tool, but it still large the number of non-diagnosed subjects, suggesting further genetic heterogeneity.

Background: ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status. Methods: Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as “mutation-positive” or “mutation-negative.” SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population). Results: Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79–2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81–5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57–2.04) probands (P < 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20–2.03, SIRnon-O = 1.83; 95% CI = 1.53–2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62–5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35–2.03) probands (P < 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09–5.47, SIRmutation-negative = 1.48; 95% CI = 1.06–5.47; P = 0.16). Conclusions: There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive. Impact: Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.

Background Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. Methods Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. Results One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. Conclusions We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.

Objective Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations. Design and methods We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital. Results Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD. Conclusions The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Background/purpose A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. Methods We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. Results Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04). Conclusion Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.

Introduction In some rare arrhythmia syndromes, arrhythmia risk in female patients increases during pregnancy, necessitating extra controls. We wanted to evaluate if the increased risk for arrhythmia during pregnancy applies in women with Brugada syndrome and their potentially affected fetuses. Methods A comprehensive literature search was performed on PubMed (MeSH search terms "Brugada syndrome," "pregnancy," "parturition," "labor," "delivery," "fetal death," and "stillbirth"). Results Overall, six case reports with a total of six patients were identified. Of these six patients (three carriers of an SCN5A variant, three not tested), two women (both with unknown SCN5A status), developed severe cardiac events during pregnancy. The first patient, with a previous history of aborted sudden cardiac arrest at the age of 12 years, developed ventricular fibrillation (VF), while the other was diagnosed with Brugada syndrome postpartum because of nocturnal agonal respiration during pregnancy. Conclusion These (limited, heterogenous) cases suggest that women with Brugada syndrome (and their possibly affected fetuses), might have an overall low tendency to develop arrhythmias during pregnancy, but important data on risk factors (SCN5A status) are lacking. Arrhythmia risk during pregnancy seems to increase in probands and those who have previously experienced cardiac events. We suggest the use of risk stratification in these women to improve patient care, lower the emotional stress and physical burden for the pregnant mother, and lower health costs. Furthermore, we plead for SCN5A analysis in all these women for use of risk stratification and to enable cascade screening especially for specialized care in children carrying an SCN5A mutation.

We herein describe a Charcot-Marie-Tooth disease (CMT) family with a MFN2 mutation with atypical ocular manifestations. The proband, his mother, his third daughter, and his deceased maternal grandfather all had symptoms of CMT and a visual impairment (either cataracts or severe astigmatism). On whole-exome sequencing for the proband having CMT and congenital cataracts, we identified a c.314C>T (p.Thr105Met) mutation in MFN2, but no mutation in the causative genes associated with cataracts. This missense mutation in MFN2 co-segregated with CMT and the atypical ocular manifestations in this family. The findings of this study might help to expand the clinical phenotype of heterogeneous MFN2-related CMT.

PURPOSE: To identify the genetic causes of multiple morphological anomalies of the flagella (MMAF) and oligoasthenoteratozoospermia (OAT). METHODS: Whole-exome sequencing (WES) was performed on the proband to identify pathogenic mutation for infertility. Western blotting and immunofluorescence analysis detected the expression level and localization of adenylate kinase 7 (AK7). RESULTS: We identified a novel homozygous missense mutation (NM_152327: c.1846G > A; p.E616K) in AK7 in two brothers with MMAF and OAT from a consanguineous family by WES. Western blotting and immunofluorescence experiments determined that the expression level of AK7 decreased in the sperm from the proband. The proband and his wife underwent two cycles of intracytoplasmic sperm injection (ICSI) treatment but got unfavorable outcomes. CONCLUSION: This study could provide precise genetic diagnosis for the patient and expand the spectrum of AK7 mutations.

Background : Breast cancer is the most common malignancy in women and thought to be hereditary in 10% of patients. Recent next-generation sequencing (NGS) studies have increased the detection of pathogenic or likely pathogenic variants in genes other than BRCA1/2 in breast cancer patients. This study evaluated pathogenic variants, likely pathogenic variants, and variants of unknown significance (VUS) in 18 hereditary cancer susceptibility genes in BRCA1/2-negative breast cancer patients. Patients and Methods : This retrospective study included 188 high-risk BRCA1/2-negative breast cancer patients tested with a multi-gene cancer panel using NGS. Results : Among 188 proband cases, 18 variants in 21 patients (11.1%) were classified as pathogenic (P) or likely pathogenic (LP) in PALB2 (໿n = 6),໿ CHEK2 (n = 5), MUTYH (n = 4), ATM (n = 3), TP53 (n = 2), BRIP1 (n = 1) and MSH2 (n = 1). Three novel P/LP variants were identified. An additional 28 variants were classified as VUS and detected in 30 (15.9%) different patients. Conclusion : This is one of the largest study from Turkey to investigate the mutation spectrum in non-BRCA hereditary breast cancer susceptibility genes. A multi-gene panel test increased the likelihood of identifying a molecular diagnosis in BRCA 1/2-negative breast cancer patients at risk for a hereditary breast cancer syndrome. More studies are needed to enable the clinical interpretation of these P/LP variants in hereditary breast cancer patients. Next-generation sequencing (NGS) studies have increased the detection of pathogenic or likely pathogenic variants in genes other than BRCA1/2 in breast cancer patients. This study included 188 high-risk BRCA1/2-negative breast cancer patients tested with a multi-gene cancer panel using NGS. Among 188 proband cases, 18 variants in 21 patients (11.1%) were classified as pathogenic (P) or likely pathogenic (LP). A multi-gene panel increased the diagnosis success in BRCA1/2-negative high-risk breast cancer patients.

Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X-linked filaminopathies caused by a variety of FLNA-variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in FLNA has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in FLNA in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis-splicing of exon 31 predicting the production of a FLNA-protein with an in-frame-deletion of 16 residues identical to the miss-splicing-effect of the recurrent TODPD c.5217G>A variant. This mis-spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X-inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the FLNA-variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy-related genes were found. Here we describe a novel variant in FLNA (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.

Aims Fabry disease (FD) is an X‐linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi‐organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families. Methods and results Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre‐excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age. Conclusions We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long‐term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.

Galloway-Mowat syndrome (GAMOS) is an extremely rare clinically heterogeneous autosomal or X-linked inherited recessive disease characterized by early-onset steroid-resistant nephrotic syndrome (SRNS), microcephaly and neurological impairment. In this study, two siblings mainly presenting with decreased head circumference, hypotonia, gross motor delay, and dysmorphic features were initially detected without pathogenic variants by karyotyping, SNP-array and WES. After a 3 year’s follow-up, the proband manifested additional proteinuria, hematuria and “deeper sulci” with a sign of brain atrophy. By reanalysis on the proband’s previous WES data, two novel compound heterozygous variants of OSGEP (c.133dupA; c.608C > T) were identified. Furthermore, functional studies showed that the variants reduced the expression of OSGEP protein and activated the DNA damage response (DDR) signaling in the lymphoblastoid cell lines (LCLs) obtained from the patient. The analysis of protein localization with confocal microscopy revealed that the EGFP-tagged/HA-tagged mutant OSGEP proteins were abnormal aggregation or retained inside the cytosol, respectively. Our study not only expanded the pathogenic variant spectrum of OSGEP but also carried on regular follow-up for kidney involvement and established a strategy for evaluation on the function of mutant OSGFP by subcellular localization assay.

Background Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is a rare autosomal recessive neurological disorder caused by mutations in the SLC52A2 gene, which is characterized by early childhood onset of sensorineural hearing loss, bulbar palsy, peripheral neuropathy, and respiratory insufficiency. We aimed to investigate the genetic cause of a 4-year-old boy who suffered from BVVLS2 whose initial presentation was severe normocytic anemia and had been overlooked for three years in a local hospital. He was misdiagnosed with pure red cell aplasia (PRCA) and treated with hormones and chemotherapy drugs, but there was no obvious effect. Methods The targeted capture of 927 genes associated with neuromuscular disorders and next-generation sequencing were performed. Sanger sequencing was employed to verify the variant mutations. Results The proband was found to be heterozygous for c.350T > C (p.L117P) in exon 3 and c.1135_1137delTGG (p.W379del) in exon 5 of SLC52A2 gene. His anemia and neurological symptoms improved significantly after treatment with low dose oral riboflavin. Conclusions This study expands the mutational spectrum of SLC52A2 and phenotypic spectrum of BVVLS2, which provides a foundation for further investigations elucidating the SLC52A2 related mechanisms of BVVLS2. A low-dosage of riboflavin supplementation was used to obtain good curative effect, which provides further future references for the clinical treatments of BVVLS.

Imbalance in dopamine (DA) signaling is proposed to play a potential role in the etiology of Autism spectrum disorder (ASD) since, as a neuromodulator, DA regulates executive function, motor activity, social peering, attention as well as perception and subjects with ASD often exhibit deficit in these traits. Level of DA in the synaptic cleft is maintained by dopamine transporter (DAT) and hence, to identify the role of DAT in ASD, we have analyzed four functional genetic variants, rs28363170, rs3836790, rs2652511, rs27072, in nuclear families with ASD probands. Subjects were diagnosed based on Diagnostic and Statistical Manual for Mental Disorders and trait severity was assessed by Childhood Autism Rating Scale 2-Standard test. Informed written consent was obtained from the parents/care givers before recruitment followed by collection of peripheral blood for genomic DNA isolation. Target sites were investigated by PCR-based methods and data obtained was analyzed by population- as well as family-based statistical methods. Case-control analysis revealed significant higher frequencies of 9 repeat (9R) and 5 repeat (5R) alleles of rs28363170 and rs3836790 respectively in the ASD probands. Family-based analysis showed statistically significant higher paternal transmission of rs28363170 9R and rs2652511 T alleles. In the presence of rs28363170 9R, rs27072 C, rs3836790 6R6R, and rs2652511 CC variants, trait scores were higher. Studied variants showed independent as well as interactive effects, which varied based on gender of the probands. We infer that altered DA availability mediated through DAT may affect autistic traits warranting further in depth investigation in the field.

Mutations in presenilin 1 (PSEN1) are the most common known genetic cause of early-onset Alzheimer’s disease. Patients with PSEN1 mutations exhibit broad phenotypes. Here, we report clinical, neuroimaging and genetic findings in a patient with a de novo mutation in PSEN1 (c.697A > G, p.M233V) presenting with early-onset parkinsonism as the initial and primary symptom. We recruited a family with one affected patient with early-onset parkinsonism. The patient underwent comprehensive neurological examination and imaging evaluation. Whole genome sequencing was performed for the proband. The patient presented with parkinsonism and mild cognitive impairment. He had a good response to levodopa. Brain MRI evaluation showed atrophy of the bilateral frontotemporal lobe and hippocampus. 18F-fluorodeoxyglucose-positron emission tomography (PET) and 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane-PET showed decreased metabolism and dopamine transporter distribution in the bilateral putamen and caudate nucleus. 11C-Pittsburgh compound B -PET showed β-amyloid protein deposition. Genetic analysis identified a heterozygous de novo variant in PSEN1 (c.697A > G, p.M233V). Screening for PSEN1 variations should be considered in patients with levodopa-responsive early-onset parkinsonism.

To describe the clinical and genetic findings of patients in the second Japanese family with Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). Two patients (a 41-year-old male proband and his third son) underwent comprehensive ophthalmic examinations, including full-field and multifocal electroretinography (ERG). Sanger sequencing was performed to detect an EFEMP1 gene variant (p.Arg345Trp), which was identified as the only causative pathogenic variant. Genetic analysis revealed that both patients carried the heterozygous variant, but the other unaffected family members did not. Although the proband exhibited innumerable radially distributed drusen in both the posterior poles and good visual acuity at initial presentation, bilateral choroidal neovascularization (CNV) developed during the 15-year follow-up. The proband received 15 intravitreal anti-vascular endothelial growth factor (VEGF) injections in the left eye (LE) and two injections in the right eye (RE). At 56 years of age, his decimal best-corrected visual acuity was 0.1 and 1.2 in the LE and RE, respectively. Full-field ERG showed that while the rod and combined responses were within normal amplitudes, the cone and 30-Hz flicker responses had slightly decreased amplitudes. Multifocal ERG revealed attenuated central responses in the LE and decreased temporal responses in the RE. In the 20-year-old son, multifocal ERG showed normal responses in both eyes. This is the first report of ML/DHRD in a patient who developed bilateral CNV and received anti-VEGF treatment in both eyes. Although multifocal ERG exhibited worsening of macular function, the generalized photoreceptor function was preserved until middle age.

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.

BACKGROUND AND PURPOSE The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with tremor-dominant symptoms. This study aimed to clarify the clinical phenotype in tremor-dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. METHODS We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re-evaluated the clinical features of the expansion-positive probands and their family members. RESULTS Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re-evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS The NIID tremor-dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.