Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency.
This was a ...questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023.
We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency.
GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.
Background & Objectives: Charcot-Marie-Tooth (CMT) disease is a group of hereditary sensorimotor neuropathies with a great variability of genotypes and phenotypes. The aims of the study were to ...provide a general perspective of the clinical manifestations and the frequency of genetic subtypes in CMT patients from a medical center in Taiyuan, northern China. Methods: Twenty-eight unrelated CMT patients were enrolled from a research center in northern China according to the CMT diagnosis criteria formulated by De Jonghe et al. in 1998. Then multiplex ligation-dependent probe amplification (MLPA) testing combined with next-generation sequencing (NGS) were performed among 18 of these patients. Results: PMP22 duplications were identified in 8 patients. In addition, 2 novel mutations were detected in the GJB1 gene (c.236T>C and c.464T>C). According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, both two GJB1 mutations were assigned as ‘likely pathogenic’. PMP22 and GJB1 were the most common causative genes in CMT1 and intermediate CMT, respectively. In addition, the first CMTX6 patient with a p.R158H mutation in the PDK3 gene was confirmed in China. Our study further shows that the p.R158H of PDK3 is likely to be a recurrent mutation. Conclusions: The results have broadened the genetic and clinical spectrums of CMT patients, which can help facilitate the diagnosis of CMT. Despite the increasing popularity of NGS, genetic screening of large cohorts of CMT patients using NGS is still rarely performed in the Chinese population. In CMT we suggest having MLPA for PMP22 as the first tier of study followed by target NGS for those with negative MLPA findings. The deciphering of the target gene candidates can further be guided by electromyographic data.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Familial exudative vitreoretinopathy (FEVR) is a disease exhibits a wide range of clinical signs, ranging mild peripheral retinal vascular anomalies to severe retinal detachments. Individuals with ...mild FEVR are frequently asymptomatic with good visual function and are often undiagnosed. However, little is known about the genetic characters of the cohort. The purpose of this study was to investigate the clinical characteristics and genetic spectrum of in patients with asymptomatic mild FEVR. Herein, sixty-two patients (124 eyes) with asymptomatic mild FEVR were studied in a case series. Comprehensive ophthalmic examinations and genetic testing were performed in all patients. Clinical examinations showed that the avascular zone was seen in all 124 eyes and was the most common abnormality observed. Increased vessel branching and straightened peripheral vessel branches were found in 122 (98.4%) eyes. Late-phase angiographic posterior and peripheral leakage (LAPPEL) was observed in 80 (64.5%) eyes and V-shape degeneration was noted in 36 (29.0%) eyes. Other manifestations including extensive anastomoses, retinal ridges, and extraretinal neovascularization, which were detected in 30 (24.2%), 10 (8.1%) and 2 (1.6%) eyes respectively. Overall, pathogenic mutations were identified in 48.4% (30/62) of individuals with asymptomatic mild FEVR. Mutations in FZD4, LRP5, TSPAN12, and KIF11 were detected in 21.0% (13/62), 12.9% (8/62), 12.9% (8/62), and 1.6% (1/62) of our patients respectively. Ten novel mutations were found. In conclusion: Pathogenic mutations in the known FEVR-associated genes were detected in nearly half (48.4%) of the asymptomatic mild FEVR cohort. Among these mutations, FZD4 was predominant, appearing in 21.0% of all individuals. Patients with asymptomatic mild FEVR should receive timely examinations, lifelong monitoring, and some of them need preventive therapy and treatment. Additionally, we discovered 10 novel variants, which may enable a deeper understanding of this disease.
•First report on the spectrum of genetic mutations in patients with asymptomatic mild FEVR cohort.•The clinical and genetic characteristics were analyzed.•Ten novel variants were detected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Keratoconus (KC) is a complex corneal disorder with genetic factors involving in its pathogenesis. The genetic etiology of KC has not been fully elucidated. In this study, we aimed to expand the ...genetic spectrum in KC by trio-based exome sequencing. Trio-based exome sequencing was conducted in 20 patients with KC and their unaffected parents to broaden the genetic spectrum of the disease. With a series of filtering criteria, de novo, recessive homozygous, and compound heterozygous variants in candidate genes were identified, and the candidate genes were classified for further analysis. Finally, we identified 60 variants in 32 candidate genes through trio-based exome sequencing. Among the candidate genes, 10 genes (ARHGEF10, ARHGEF17, ASPM, FLNA, NDRG1, NEB, PLS3, STARD8, SYNE1, TTN) were classified as cytoskeleton-related genes, 4 genes (COL28A1, SDK1, STAB1, TENM2) were classified as cell adhesion-related genes, and 18 genes (APLP2, BCORL1, CCNB3, FOXN1, FUT8, GALNT10, HEPH, HHIP, HMGB3, HS6ST2, JADE3, KIAA0040, MCF2L, MYOF, QRICH2, RPS6KA6, SMARCA1, TNRC6A) were classified into other genes group. Additionally, the candidate rare deleterious variants in TTN were highly repeated in 25% trios. In conclusion, the study provided new insights into the genetic spectrum of KC which might underlie the genetic etiology for the disease. The findings would improve our understanding of pathogenesis in KC and provide critical clues to future functional validation.
•A total of 60 variants in 32 candidate genes were identified to account for KC.•The candidate genes were classified into cytoskeleton-related genes, cell adhesion-related genes and other genes group.•The TTN which was highly repeated in 25% trios might result in KC via influencing the corneal stiffness.•The study provided new insights on the genetic spectrum of KC which might underlie the genetic etiology for the disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To describe the natural history, genetic landscape, and phenotypic spectrum of Eyes shut homolog (EYS)–associated retinal degeneration (EYS-RD).
Retrospective, single-center cohort study complemented ...by a cross-sectional examination.
Patients with biallelic EYS variants were recruited at an inherited RD referral center in Portugal.
Every patient underwent a cross-sectional examination comprising a comprehensive ophthalmic examination including best-corrected visual acuity (BCVA), dilated slit-lamp anterior segment, and fundus biomicroscopy; ultrawide-field color fundus photography and fundus autofluorescence imaging; and spectral domain–OCT. In the setting of a retinitis pigmentosa (RP) diagnosis, every patient was classified as typical or atypical RP according to imaging criteria. Baseline demographics, age at onset of symptoms, family history, history of consanguinity, symptoms, age at diagnosis, BCVA at baseline and throughout follow-up, and EYS variants were collected from each individual patient file.
Clinical/demographic, genetic, multimodal imaging data, and BCVA variation were compared between typical and atypical RP. Additionally, BCVA variation during follow-up was used as an endpoint to describe EYS-RD natural history.
Fifty-eight patients (59% men; mean age 52 ± 14 years) from 48 White families of Portuguese ancestry were included. Twenty distinct EYS variants were identified, 8 of which are novel. In 32.8% of patients, onset of symptoms was in early adulthood (21–30 years). A clinical diagnosis of RP was established in 57 patients and cone-rod dystrophy in 1 patient. Regarding RP, 75.0% of the patients were graded as typical and 25.0% as atypical. Atypical EYS-RP commonly presents with inferior crescent-shaped macular atrophy with superior midperipheral sparing. In EYS-RD, a negative correlation was found between age and BCVA (r = −0.50; P < 0.001), with an average loss of 1.45 letters per year. When stratifying for RP phenotype, lower average loss of letters per year (P < 0.001), higher BCVA (P < 0.001), and larger ellipsoid zone widths (P < 0.001) were found in atypical RP.
This study expands the genetic spectrum of EYS-RD by reporting 8 novel variants. A high frequency of atypical phenotypes was identified. These patients have better BCVA and larger ellipsoidal zone widths, thus presenting an overall better prognosis.
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Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) ...worldwide. In this study, we utilized genome‐wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL‐associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene‐based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.
In this study, we utilized genome‐wide genotyping, Sanger and exome sequencing to
identify 163 DNA variants in 41 previously reported hearing loss (HL) genes segregating in 321 Pakistani families. SLC26A4, MYO7A, GJB2, CIB2 and HGF were identified as the five most common genes in our cohort. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene‐based therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To explore the genetic spectrum of cerebral palsy (CP) in a Chinese pediatric cohort.
This was a retrospective observational study of patients with CP from the Children's Hospital of Fudan University ...between June 2015 and December 2019. Their clinical data and exome sequencing data were collected and analyzed.
A total of 217 patients with CP were enrolled, and genetic variants were identified in 78 subjects (35.9%): 65 patients with single-nucleotide variants (SNVs), 12 patients with copy number variants, and 1 patient with both an SNV and a copy number variant. The genetic diagnosis rates were significantly greater in patients without clinical risk factors than in patients with clinical risk factors (χ2 = 21.705, P = .000) and were significantly greater in patients with a family history than in those without a family history (χ2 = 4.493, P = .034). Variants in genes related to neurologic disorders were the most commonly detected variants, affecting 41 patients (62.1%, 41/66). Among the patients with SNVs detected, the top 12 genes were found to cover 62.1% (41/66) of cases, and 39.4% (26/66) of patients with SNVs had medically actionable genetic findings.
The overall genetic diagnostic rate in this study was 35.9%, and patients without any clinical risk factors or with a family history were more likely to have genetic risk factors. The top 12 genes detected in this study as well as genes related to neurologic disorders or other medically actionable disorders should be noted in the analysis of genetic testing results in patients with CP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively ...more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients.
We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics.
A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)—mainly adrenoleukodystrophy and Krabbe disease—accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies.
We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.
Wu et al. describe the clinical and radiological features of genetic leukoencephalopathies in a large cohort of 309 adults, and find that the most frequently mutated genes are NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%).
Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and ...genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease.
The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized.
54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up. Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in
and
. The genetic diagnostic rate in these 54 patients was 35.18%.
Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.
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