112 results on '"Luk HM"'
Search Results
2. Pregnancies with positive non-invasive prenatal testing result for sex chromosome abnormalities in a tertiary hospital in Hong Kong
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So, PL, primary, Lai, S, additional, Wong, PP, additional, Siong, KH, additional, Leung, HK, additional, Sin, WK, additional, Kan, Anita SY, additional, Luk, HM, additional, Lo, Ivan FM, additional, Au Leung, KC, additional, and Wong, SF, additional
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- 2022
- Full Text
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3. Infantile to late adulthood onset facioscapulohumeral dystrophy type 1: a case series
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Leung, WY, primary, Luk, HM, additional, Vardhanabhuti, Varut, additional, Gao, Y, additional, Hui, KF, additional, Lau, WY, additional, Young, Terence PH, additional, Li, Jessica TC, additional, Fung, Eva LW, additional, Chiu, Annie TG, additional, Lo, Ivan FM, additional, Chung, Brian HY, additional, Cheung, YF, additional, and Chan, Sophelia HS, additional
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- 2021
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4. Isolated hereditary diffuse palmoplantar keratoderma in Hong Kong Chinese patients: a case series
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Yu, PT, primary, Ho, Stephanie, additional, Ng, SC, additional, Lo, FM, additional, and Luk, HM, additional
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- 2021
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5. SENSV: Detecting Structural Variations with Precise Breakpoints using Low-Depth WGS Data from a Single Oxford Nanopore MinION Flowcell
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Tak-Wah Lam, Law W, Luk Hm, Yat-Sing Wong, Huan Yu, Lo If, Ye Zhang, Chak-Lim Wong, Leung Hc, Wai Shing Leung, Ruibang Luo, and Ma Kk
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Structural variation ,Computer science ,Minion ,Clinical diagnosis ,Simulated data ,Gene duplication ,Breakpoint ,Flow cell ,Nanopore sequencing ,Computational biology - Abstract
Structural variation (SV) is a major cause of genetic disorders. In this paper, we show that low-depth (specifically, 4x) whole-genome sequencing using a single Oxford Nanopore MinION flow cell suffices to support sensitive detection of SV, in particular, pathogenic SV for supporting clinical diagnosis. Existing SV calling software, when using 4x ONT WGS data, often fails to detect pathogenic SV especially in the form of long deletion, terminal deletion, duplication, and unbalanced translocation. Our new SV calling software SENSV is able to achieve high sensitivity for all types of SV and a breakpoint precision typically ±100 bp, both features are important for clinical concerns. The improvement achieved by SENSV stems from several new algorithms. We evaluated SENSV and other software using both real and simulated data. The former was based on 24 patient samples, each diagnosed with a genetic disorder. SENSV found the pathogenic SV in 22 out of 24 cases (all heterozygous, size from hundreds of Kbp to a few Mbp), reporting breakpoints within 100 bp of the true answers. No existing software can detect the pathogenic SV in more than 10 out of 24 cases, even when the breakpoint requirement is relaxed to ±2,000 bp.
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- 2021
6. ECNano: A Cost-Effective Workflow for Target Enrichment Sequencing and Accurate Variant Calling on 4,800 Clinically Significant Genes Using a Single MinION Flowcell
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Ruibang Luo, Zheng Z, Alan W. Leung, Lui W, Luk Hm, Tak-Wah Lam, Henry C. M. Leung, Chak-Lim Wong, and Lo If
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Workflow ,Bioinformatics analysis ,Computer science ,Minion ,Computational biology ,Nanopore sequencing ,Gene ,Target enrichment ,Turnaround time ,Exome sequencing - Abstract
BackgroundThe application of long-read sequencing using the Oxford Nanopore Technologies (ONT) MinION sequencer is getting more diverse in the medical field. Having a high sequencing error of ONT and limited throughput from a single MinION flowcell, however, limits its applicability for accurate variant detection. Medical exome sequencing (MES) targets clinically significant exon regions, allowing rapid and comprehensive screening of pathogenic variants. By applying MES with MinION sequencing, the technology can achieve a more uniform capture of the target regions, shorter turnaround time, and lower sequencing cost per sample.MethodWe introduced a cost-effective optimized workflow, ECNano, comprising a wet-lab protocol and bioinformatics analysis, for accurate variant detection at 4,800 clinically important genes and regions using a single MinION flowcell. The ECNano wet-lab protocol was optimized to perform long-read target enrichment and ONT library preparation to stably generate high-quality MES data with adequate coverage. The subsequent variant-calling workflow, Clair-ensemble, adopted a fast RNN-based variant caller, Clair, and was optimized for target enrichment data. To evaluate its performance and practicality, ECNano was tested on both reference DNA samples and patient samples.ResultsECNano achieved deep on-target depth of coverage (DoC) at average >100x and >98% uniformity using one MinION flowcell. For accurate ONT variant calling, the generated reads sufficiently covered 98.9% of pathogenic positions listed in ClinVar, with 98.96% having at least 30x DoC. ECNano obtained an average read length of 1,000 bp. The long reads of ECNano also covered the adjacent splice sites well, with 98.5% of positions having ≥ 30x DoC. Clair-ensemble achieved >99% recall and accuracy for SNV calling. The whole workflow from wet-lab protocol to variant detection was completed within three days.ConclusionWe presented ECNano, an out-of-the-box workflow comprising (1) a wet-lab protocol for ONT target enrichment sequencing and (2) a downstream variant detection workflow, Clair-ensemble. The workflow is cost-effective, with a short turnaround time for high accuracy variant calling in 4,800 clinically significant genes and regions using a single MinION flowcell. The long-read exon captured data has potential for further development, promoting the application of long-read sequencing in personalized disease treatment and risk prediction.
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- 2021
7. Spread of X inactivation on chromosome 15 is associated with a more severe phenotype in a girl with an unbalanced t(X; 15) translocation
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Yeung, KS, Chee, YY, Luk, HM, Kan, Anita SY, Tang, Mary HY, Lau, Elizabeth T, Shuen, Andrew Y, Lo, Ivan FM, Chan, Kelvin YK, and Chung, Brian HY
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- 2014
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8. Familial patellar dislocation associated with t(15;20) (q24;q13.1)
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Chan, CM Jimmy, primary, Chau, YM Jackie, additional, Woo, SB, additional, Luk, HM, additional, and Lo, Ivan FM, additional
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- 2018
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9. Mechanisms for the generation of two quadruplications associated with split-hand malformation
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Lupski, JR, Gu, S, Posey, JE, Yuan, B, Carvalho, CMB, Luk, HM, Erikson, K, Chung, BHY, Lo, IFM, Leung, GKC, and Pickering, CR
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- 2016
10. A young woman with mucocutaneous pigmentation and intestinal polyps
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Luk, HM, primary, Lo, Ivan FM, additional, Yu, Kelvin MC, additional, Tong, Tony MF, additional, and Lam, Stephen TS, additional
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- 2013
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11. Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.
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Ho SKL, Ng SYL, Yung TK, Mok MTS, Yiu WC, Cheng HHY, Cheng SSW, Luk HM, Lo IFM, and Kan ASY
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- Humans, Female, Male, Adult, Mutation genetics, Factor VIII genetics, Retrospective Studies, Genetic Association Studies, Phenotype, Hemophilia A genetics, Hemophilia A pathology, Hemophilia A epidemiology, Heterozygote
- Abstract
Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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12. Natural history of adults with KBG syndrome: A physician-reported experience.
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Bayat A, Grimes H, de Boer E, Herlin MK, Dahl RS, Lund ICB, Bayat M, Bolund ACS, Gjerulfsen CE, Gregersen PA, Zilmer M, Juhl S, Cebula K, Rahikkala E, Maystadt I, Peron A, Vignoli A, Alfano RM, Stanzial F, Benedicenti F, Currò A, Luk HM, Jouret G, Zurita E, Heuft L, Schnabel F, Busche A, Veenstra-Knol HE, Tkemaladze T, Vrielynck P, Lederer D, Platzer K, Ockeloen CW, Goel H, and Low KJ
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- Humans, Adult, Male, Female, Middle Aged, Young Adult, Haploinsufficiency genetics, Seizures genetics, Seizures epidemiology, Physicians, Adolescent, Facies, Abnormalities, Multiple, Bone Diseases, Developmental, Tooth Abnormalities, Intellectual Disability genetics, Intellectual Disability epidemiology, Phenotype
- Abstract
Purpose: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS., Methods: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data., Results: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets., Conclusion: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2024
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13. Case report: Treatment response of NF-1-associated bladder ganglioneuroma to trametinib.
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Chan MCY, Fung KKF, Ng WF, Luk HM, Ku DTL, and Liu APY
- Abstract
We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chan, Fung, Ng, Luk, Ku and Liu.)
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- 2024
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14. Molecular autopsy in Chinese sudden cardiac death in the young.
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Kwok SY, Ho S, Shih FY, Yeung PK, Cheng SSW, Poon WM, Lo IFM, and Luk HM
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Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5-year result (2017-2021) of molecular autopsy services provided for victims of SCDY (age 1-40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016-2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)-causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD-causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at-risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted., (© 2024 Wiley Periodicals LLC.)
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- 2024
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15. A de novo pathogenic variant in neuronal differentiation factor 2 in a Chinese patient with early infantile epileptic encephalopathy.
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Poon JYY, Mok MTS, Ho SKL, Cheng SSW, Lo IFM, and Luk HM
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- Female, Humans, Infant, Asian People genetics, East Asian People, Mutation, Spasms, Infantile genetics, Spasms, Infantile diagnosis
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- 2024
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16. Prenatal diagnosis of Myhre syndrome with a heterozygous pathogenic variant in SMAD4 gene presented with thick nuchal translucency and cardiac abnormalities.
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Hui PW, Mok YK, Luk HM, Au SLK, Lau EYT, Chung B, and Kan ASY
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- Pregnancy, Female, Humans, Adult, Nuchal Translucency Measurement, Vena Cava, Superior, Prenatal Diagnosis, Ultrasonography, Prenatal, Smad4 Protein genetics, Intellectual Disability diagnostic imaging, Intellectual Disability genetics, Pericardial Effusion, Heart Defects, Congenital
- Abstract
Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)
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- 2023
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17. Public and Healthcare Provider Receptivity toward the Retention of Dried Blood Spot Cards and Their Usage for Extended Genetic Testing in Hong Kong.
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Belaramani KM, Fung CW, Kwok AMK, Lee SYR, Yau EKC, Luk HM, Mak CM, Yeung MCW, and Ngan OMY
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Dried blood spot (DBS) cards from newborn screening (NBS) programs represent a wealth of biological data. They can be stored easily for a long time, have the potential to support medical and public health research, and have secondary usages such as quality assurance and forensics, making it the ideal candidate for bio-banking. However, worldwide policies vary with regard to the duration of storage of DBS cards and how it can be used. Recent advances in genomics have also made it possible to perform extended genetic testing on DBS cards in the newborn period to diagnose both actionable and non-actionable childhood and adult diseases. Both storage and secondary uses of DBS cards raise many ethical, clinical, and social questions. The openness of the key stakeholders, namely, parents and healthcare providers (HCPs), to store the DBS cards, and for what duration and purposes, and to extended genetic testing is largely dependent on local cultural-social-specific factors. The study objective is to assess the parents' and HCPs' awareness and receptivity toward DBS retention, its secondary usage, and extended genetic testing. A cross-sectional, self-administrated survey was adopted at three hospitals, out of which two were public hospitals with maternity services, between June and December 2022. In total, 452 parents and 107 HCPs completed and returned the survey. Overall, both HCPs and parents were largely knowledgeable about the potential benefits of DBS card storage for a prolonged period and its secondary uses, and they supported extended genetic testing. Knowledge gaps were found in respondents with a lower education level who did not know that a DBS card could be stored for an extended period ( p < 0.001), could support scientific research ( p = 0.033), and could aid public health research, and future policy implementation ( p = 0.030). Main concerns with regard to DBS card storage related to potential privacy breaches and anonymity (Parents 70%, HCPs 60%). More parents, compared to HCPs, believed that storing DBS cards for secondary research does not lead to a reciprocal benefit to the child ( p < 0.005). Regarding extended genetic testing, both groups were receptive and wanted to know about actionable childhood- and adult-onset diseases. More parents (four-fifths) rather than HCPs (three-fifths) were interested in learning about a variant with unknown significance ( p < 0.001). Our findings report positive support from both parents and HCPs toward the extended retention of DBS cards for secondary usage and for extended genetic testing. However, more efforts to raise awareness need to be undertaken in addition to addressing the ethical concerns of both parents and HCPs to pave the way forward toward policy-making for DBS bio-banking and extended genetic testing in Hong Kong.
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- 2023
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18. A Baby With Complete Androgen Insensitivity Syndrome and the Fortuitous Discovery of 45,X/46,XY Mosaicism.
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Wong WY, Wong LM, Tam YH, and Luk HM
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Disorders of sex development (DSD) are caused by defects in the complex sexual differentiation cascade, resulting in discordance among an individual's genetic, gonadal, and genital sexes. It affects one in 4,500 live births. A wide spectrum of genital phenotypes can be found depending on the underlying pathogenic mechanism and the developmental stage that is affected. We herein report a newborn with female external genitalia but palpable gonads at labia majora with normal testicular function and structure, which is typical of complete androgen insensitivity syndrome (CAIS). The genetic study revealed 45,X/46,XY mosaicism and c.2081A>C missense androgen receptor gene mutation, indicating the likelihood of co-existing CAIS. This case demonstrated the importance of correlating genital phenotype and the underlying pathogenic mechanism, to provide appropriate management of DSD. Important considerations on managing the gonads about the risks of gonadal malignancies are also discussed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wong et al.)
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- 2023
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19. Extending the phenotype of Shashi-Pena syndrome: a case report and review of literature.
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Ho SKL, Cheng SSW, Cheng THT, Leung LT, Lam EKY, Mok MTS, Lo IFM, and Luk HM
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- Humans, Phenotype, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics
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- 2023
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20. Fibrodysplasia ossificans progressiva in Hong Kong-A case report series.
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Chan JCK, Kuong EE, Chan JPK, Luk HM, Fung JLF, Tung JY, and Chung BHY
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Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare condition. The diagnosis could be challenging due to its rarity and non-specific presenting symptoms. However, early diagnosis and appropriate management help in preserving patients' function and quality of life. Herein, we report the diagnostic journeys and clinical courses of 8 patients with FOP in Hong Kong and illustrate the challenges involved., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chan, Kuong, Chan, Luk, Fung, Tung and Chung.)
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- 2023
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21. Patient-Initiated Follow-Up in Ovarian Cancer.
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Luk HM, Ngu SF, Lau LSK, Tse KY, Chu MMY, Kwok ST, Ngan HYS, and Chan KKL
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- Female, Humans, Follow-Up Studies, Ovarian Neoplasms therapy, Cancer Survivors
- Abstract
This study aimed to assess the feasibility of patient-initiated follow-up (PIFU) in combination with regular tumour marker monitoring as an alternative to conventional hospital follow-up for ovarian cancer survivors. Women who had recently completed treatment for ovarian cancer and had a raised pre-treatment tumour marker were recruited. Participants were allocated to PIFU (intervention group) or conventional hospital follow-up (control group) according to their own preference. Both groups had regular tumour marker monitoring. The change in fear of cancer recurrence (FCR) score as measured by the FCR inventory, and the supportive care need (SCN) scores as measured by the SCN survey at baseline and at 6 months between PIFU and hospital follow-up were compared. Out of 64 participants, 37 (58%) opted for hospital follow-up and 27 (42%) opted for PIFU. During the 6-month study period, there was no significant difference in the change of FCR between the two groups ( p = 0.35). There was a significant decrease in the sexuality unmet needs score in the intervention group from baseline to 6-month FU (mean difference -8.7, 95% confidence interval -16.1 to -1.4, p = 0.02). PIFU with tumour marker monitoring is a feasible follow-up approach in ovarian cancer survivorship care. FCR and SCN were comparable between PIFU and conventional hospital follow-up.
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- 2023
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22. Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.
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Wong TS, Belaramani KM, Chan CK, Chan WK, Chan WL, Chang SK, Cheung SN, Cheung KY, Cheung YF, Chong SJ, Chow CJ, Chung HB, Fan SF, Fok WJ, Fong KW, Fung TS, Hui KF, Hui TH, Hui J, Ko CH, Kwan MC, Kwok MA, Kwok SJ, Lai MS, Lam YO, Lam CW, Lau MC, Law CE, Lee WC, Lee HH, Lee CN, Leung KH, Leung KY, Li SH, Ling TJ, Liu KT, Lo FM, Lui HT, Luk CO, Luk HM, Ma CK, Ma K, Ma KH, Mew YN, Mo A, Ng SF, Poon WG, Rodenburg R, Sheng B, Smeitink J, Szeto CC, Tai SM, Tse CA, Tsung LL, Wong HJ, Wong WW, Wong KK, Wong SS, Wong CV, Wong WS, Wong CF, Wu SP, Wu HJ, Yau MM, Yau KE, Yeung WL, Yeung HJ, Yip KE, Young PT, Yuan G, Yuen YL, Yuen CL, and Fung CW
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- Humans, Hong Kong, Prevalence, Retrospective Studies, Asian People, Mitochondrial Diseases
- Abstract
Objective: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region., Methods: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators., Results: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%., Conclusion: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry., (© 2023. The Author(s).)
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- 2023
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23. Implementation of Public Funded Genome Sequencing in Evaluation of Fetal Structural Anomalies.
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So PL, Hui ASY, Ma TWL, Shu W, Hui APW, Kong CW, Lo TK, Kan ANC, Kan EYL, Chong SC, Chung BHY, Luk HM, Choy KW, Kan ASY, and Leung WC
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- Pregnancy, Female, Humans, Retrospective Studies, Exome Sequencing methods, Fetus abnormalities, Ultrasonography, Prenatal, Prenatal Diagnosis
- Abstract
With the advancements in prenatal diagnostics, genome sequencing is now incorporated into clinical use to maximize the diagnostic yield following uninformative conventional tests (karyotype and chromosomal microarray analysis). Hong Kong started publicly funded prenatal genomic sequencing as a sequential test in the investigation of fetal structural anomalies in April 2021. The objective of the study was to evaluate the clinical performance and usefulness of this new service over one year. We established a web-based multidisciplinary team to facilitate case selection among the expert members. We retrospectively analyzed the fetal phenotypes, test results, turnaround time and clinical impact in the first 15 whole exome sequencing and 14 whole genome sequencing. Overall, the molecular diagnostic rate was 37.9% (11/29). De novo autosomal dominant disorders accounted for 72.7% (8/11), inherited autosomal recessive disorders for 18.2% (2/11), and inherited X-linked disorders for 9.1% (1/11). The median turnaround time for ongoing pregnancy was 19.5 days (range, 13-31 days). Our study showed an overall clinical impact of 55.2% (16/29), which influenced reproductive decision-making in four cases, guided perinatal management in two cases and helped future family planning in ten cases. In conclusion, our findings support the important role of genome sequencing services in the prenatal diagnosis of fetal structural anomalies in a population setting. It is important to adopt a multidisciplinary team approach to support the comprehensive genetic service.
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- 2022
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24. Applications and Safety of Sentinel Lymph Node Biopsy in Endometrial Cancer.
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Chiu WK, Kwok ST, Wang Y, Luk HM, Chan AHY, and Tse KY
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Lymph node status is important in predicting the prognosis and guiding adjuvant treatment in endometrial cancer. However, previous studies showed that systematic lymphadenectomy conferred no therapeutic values in clinically early-stage endometrial cancer but might lead to substantial morbidity and impact on the quality of life of the patients. The sentinel lymph node is the first lymph node that tumor cells drain to, and sentinel lymph node biopsy has emerged as an acceptable alternative to full lymphadenectomy in both low-risk and high-risk endometrial cancer. Evidence has demonstrated a high detection rate, sensitivity and negative predictive value of sentinel lymph node biopsy. It can also reduce surgical morbidity and improve the detection of lymph node metastases compared with systematic lymphadenectomy. This review summarizes the current techniques of sentinel lymph node mapping, the applications and oncological outcomes of sentinel lymph node biopsy in low-risk and high-risk endometrial cancer, and the management of isolated tumor cells in sentinel lymph nodes. We also illustrate a revised sentinel lymph node biopsy algorithm and advocate to repeat the tracer injection and explore the presacral and paraaortic areas if sentinel lymph nodes are not found in the hemipelvis.
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- 2022
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25. Genotype/phenotype correlation in 123 Chinese patients with Tuberous Sclerosis Complex.
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Ng SY, Luk HM, Hau EW, Cheng SS, Yu KP, Ho S, Mok MT, and Lo IF
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- Female, Humans, Male, Pregnancy, China, Genotype, Mutation, Phenotype, Tuberous Sclerosis Complex 1 Protein genetics, Tuberous Sclerosis Complex 2 Protein genetics, Tumor Suppressor Proteins genetics, Angiomyolipoma genetics, Intellectual Disability, Kidney Neoplasms, Rhabdomyoma genetics, Tuberous Sclerosis genetics, Tuberous Sclerosis pathology
- Abstract
Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder with autosomal dominant inheritance. We performed mutation analyses on 123 Chinese patients with "definite TSC" according to the latest diagnostic criteria. Pathogenic / likely-pathogenic variants were identified in 72.2% of all index patients (70/97), in which 35.7% (25/70) had TSC1 variants and 64.3% (45/70) had TSC2 variants. 84.5% (82/97) cases were sporadic and 15.5% (15/97) cases were familial. 62 unique variants were reported, in which 41.9% (26/62) were novel. Male patients had significantly more subependymal nodules (p=0.029) than females, whereas renal angiomyolipoma (p=0.032) occurred predominantly in females. Sporadic cases also had more renal angiomyolipoma (p=0.004), cortical tubers (p=0.008), hypopigmented macules (p=0.018) and fibrous cephalic plaques (p=0.028) than cases with known inheritance. Patients with TSC2 pathogenic variants were more likely to have mental retardation (p<0.001), cardiac rhabdomyoma (p=0.004), renal angiomyolipoma (p=0.006) and facial angiofibromas (p=0.026) than those with TSC1 pathogenic variants, while mutation-negative cases showed a mixed phenotype between those with TSC1 and TSC2 variants. There were no significant phenotypic differences between patients with and without TSC1/TSC2 variants, but TSC2 missense and in-frame variants were associated with higher frequencies of mental retardation (P<0.001), renal angiomyolipoma (p=0.001), cardiac rhabdomyoma (p=0.012) and facial angiofibroma (p=0.021) than those with TSC1 frameshift and splice site variants. Furthermore, a higher frequency of mental retardation (p=0.013) was observed in patients with TSC2 missense and in-frame variants than those with frameshift and splice site variants. All 14 antenatal-onset patients had cardiac rhabdomyoma. They had fewer seizures (p=0.028) than patients with paediatric-onset, but were more likely to have mental retardation (p=0.035) than individuals with adult-onset disease. Generally, paediatric-onset patients had more neurological manifestations, while initial presentations of adult-onset TSC were more diverse., Competing Interests: Declaration of competing interest We know no conflicts of interest associated with this manuscript., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Published
- 2022
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26. KBG syndrome in a Chinese population: A case series.
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Ho S, Luk HM, and Lo IFM
- Subjects
- China epidemiology, Comparative Genomic Hybridization, Facies, Humans, Phenotype, Repressor Proteins genetics, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Bone Diseases, Developmental diagnosis, Bone Diseases, Developmental genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Tooth Abnormalities diagnosis, Tooth Abnormalities genetics
- Abstract
KBG syndrome (OMIM #148050) is an autosomal dominant neurodevelopmental disorder characterized by the presence of macrodontia of the permanent central upper incisors, characteristic facial features, delay in development, intellectual disability, short stature, and various skeletal abnormalities. Over 200 affected individuals have been described worldwide, though underdiagnosis is suspected because the characteristic features are variably present and affected individuals can have a mild phenotype. This case series provides a summary of the clinical and molecular characteristics of 10 Chinese KBG syndrome patients recruited from a single center. To our knowledge, this is the first case series for Chinese KBG patients. This case series aimed at exploring potential ethnicity-related variability in KBG syndrome., (© 2022 Wiley Periodicals LLC.)
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- 2022
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27. Successful Treatment of Drug-Resistant Seizures Secondary to Ring 20 Mosaicism with Perampanel as an Add-On Antiepileptic Drug.
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Ling J, Yeung WL, Hon KL, Lo IFM, Luk HM, Fung CW, and Leung AKC
- Abstract
We report a girl with drug-resistant seizures, progressive behavioral changes, and cognitive decline. Investigations showed abnormal EEG with frequent high-voltage bifrontotemporal sharp and slow waves, especially during sleep. Seizures were difficult to control, despite the usage of various antiepileptic drugs. Perampanel as an add-on antiepileptic drug appeared efficacious. Due to the recognizable pattern of seizures and EEG findings, a karyotype study was performed which revealed 46 chromosomes with a ring 20 chromosome mosaicism. Ring 20 chromosome is associated with drug-resistant refractory seizures, cognitive decline, and behavioral problems. This case highlights the difficulty and challenge faced in managing drug-resistant refractory seizures associated with ring 20 chromosome. While ring 20 chromosome is often underdiagnosed, one should have a high index of awareness and suspicion of such rare epilepsy syndrome, so that an early diagnosis can be made., Competing Interests: Professor Alexander KC Leung is an academic editor of Case Report in Paediatrics. The authors declare that there are no conflicts of interest., (Copyright © 2022 Janet Ling et al.)
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- 2022
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28. The first case report of Strømme syndrome in a Chinese patient: Expanding the phenotype and literature review.
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Ho S, Luk HM, and Lo IFM
- Subjects
- China, Humans, Intestinal Atresia, Male, Pedigree, Phenotype, Eye Abnormalities diagnosis, Eye Abnormalities genetics, Microcephaly diagnosis, Microcephaly genetics, Microcephaly pathology
- Abstract
Strømme syndrome (MIM #243605) is a rare autosomal recessive ciliopathy resulting from compound heterozygous or homozygous pathogenic alterations in the CENPF gene (# 600236). Although there are a number of case reports featuring individuals with clinically compatible Strømme syndrome, only 13 affected individuals had molecular confirmation worldwide. Herein, we report a 24 years old Chinese gentleman with molecularly confirmed Strømme syndrome with compound heterozygous pathogenic nonsense variants in NM_016343.3(CENPF):c.436C > T, p.(Gln146*) and c.9280C > T, p.(Arg3094*). He presented with microcephaly, unilateral microphthalmia, single central upper incisor and bilateral preaxial polydactyly. To our knowledge, this is the first reported Chinese individual with molecularly confirmed Strømme syndrome., (© 2022 Wiley Periodicals LLC.)
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- 2022
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29. Prenatal presentation in two fetuses with features of Beckwith Wiedemann syndrome-An unexpected diagnosis of androgenetic chimera and its clinical implications.
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Yu PT, Shu W, Mok SL, Hui PW, Chan LW, Kwok KY, Chan KYK, Lo TK, Chung BHY, Luk HM, and Kan ASY
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- Androgens, Chimera, DNA Methylation genetics, Female, Fetus, Genomic Imprinting genetics, Humans, Placenta, Pregnancy, Uniparental Disomy genetics, Beckwith-Wiedemann Syndrome diagnosis, Beckwith-Wiedemann Syndrome genetics
- Abstract
Beckwith Wiedemann Syndrome (BWS, OMIM 130650) is an imprinting disorder that may present antenatally with a constellation of sonographic features namely polyhydramnios, macrosomia, macroglossia, omphalocele, placental mesenchymal dysplasia, cardiomegaly, nephromegaly, fetal hydrops, and other rare anomalies. Paternal uniparental disomy in chromosome 11p15 imprinting region accounts for 20% of all BWS, and 8% among those were due to genome-wide paternal uniparental disomy (GWpUPD). GWpUPD is a rare condition and usually results in prenatal lethality. The 31 liveborns reported in the literature demonstrate female predominance in surviving GWpUPD. Here, we reported two prenatal cases which initially presented with features suggestive of BWS, which subsequently were confirmed to have GWpUPD. Further trio SNP genotyping analysis using SNP-based chromosomal microarray revealed androgenetic biparental chimera as the underlying cause. Finally, we highlighted the importance of recognizing GWpUPD as a possible cause in a fetus presenting with BWS phenotype, as it carried a different disease prognosis, tumor predisposition, manifestations of other imprinting disorders, and possibility in unmasking autosomal recessive disorders from the paternal alleles., (© 2022 Wiley Periodicals LLC.)
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- 2022
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30. Investigation of Chromosomal Structural Abnormalities in Patients With Undiagnosed Neurodevelopmental Disorders.
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Cao Y, Luk HM, Zhang Y, Chau MHK, Xue S, Cheng SSW, Li AM, Chong JSC, Leung TY, Dong Z, Choy KW, and Lo IFM
- Abstract
Background: Structural variations (SVs) are various types of the genomic rearrangements encompassing at least 50 nucleotides. These include unbalanced gains or losses of DNA segments (copy number changes, CNVs), balanced rearrangements (such as inversion or translocations), and complex combinations of several distinct rearrangements. SVs are known to play a significant role in contributing to human genomic disorders by disrupting the protein-coding genes or the interaction(s) with cis-regulatory elements. Recently, different types of genome sequencing-based tests have been introduced in detecting various types of SVs other than CNVs and regions with absence of heterozygosity (AOH) with clinical significance. Method: In this study, we applied the mate-pair low pass (∼4X) genome sequencing with large DNA-insert (∼5 kb) in a cohort of 100 patients with neurodevelopmental disorders who did not receive informative results from a routine CNV investigation. Read-depth-based CNV analysis and chimeric-read-pairs analysis were used for CNV and SV analyses. The region of AOH was indicated by a simultaneous decrease in the rate of heterozygous SNVs and increase in the rate of homozygous SNVs. Results: First, we reexamined the 25 previously reported CNVs among 24 cases in this cohort. The boundaries of these twenty-five CNVs including 15 duplications and 10 deletions detected were consistent with the ones indicated by the chimeric-read-pairs analysis, while the location and orientation were determined in 80% of duplications (12/15). Particularly, one duplication was involved in complex rearrangements. In addition, among all the 100 cases, 10% of them were detected with rare or complex SVs (>10 Kb), and 3% were with multiple AOH (≥5 Mb) locating in imprinting chromosomes identified. In particular, one patient with an overall value of 214.5 Mb of AOH identified on 13 autosomal chromosomes suspected parental consanguinity. Conclusion: In this study, mate-pair low-pass GS resolved a significant proportion of CNVs with inconclusive significance, and detected additional SVs and regions of AOH in patients with undiagnostic neurodevelopmental disorders. This approach complements the first-tier CNV analysis for NDDs, not only by increasing the resolution of CNV detection but also by enhancing the characterization of SVs and the discovery of potential causative regions (or genes) contributory to could be complex in composition NDDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Luk, Zhang, Chau, Xue, Cheng, Li, Chong, Leung, Dong, Choy and Lo.)
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- 2022
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31. Old and new perspectives on Neurofibromatosis type 1: Clinical and molecular characterization of 832 patients from a single centre over 16 years.
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Ho SK, Luk HM, Ng SY, Yu KP, Cheng SS, Ng PP, Mok MT, Hau EW, and Lo IF
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- Genetic Association Studies, Genotype, Hong Kong epidemiology, Humans, Phenotype, Neurofibromatosis 1 diagnosis, Neurofibromatosis 1 genetics
- Abstract
Neurofibromatosis type 1 (NF1; OMIM #162200) is the commonest multi-systemic neurocutaneous tumour-predisposition disorder. It has an age-related complete penetrance but a highly variable inter- and intra-familial expressivity. This article summarizes the clinical features and molecular characteristics of 832 clinically or molecularly confirmed NF1 patients from 697 unrelated families recruited from a single centre in Hong Kong diagnosed during the 16 years period from Jan 2005 to Jan 2021. In this study, we have estimated the incidences of clinical features, reported on the molecular findings and explored new genotype-phenotype correlations., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
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- 2022
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32. A further case of Skraban-Deardorff syndrome and review of the literature.
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Shirley Cheng SW, Luk HM, and Lo FMI
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- 2022
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33. Detecting structural variations with precise breakpoints using low-depth WGS data from a single oxford nanopore MinION flowcell.
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Leung HCM, Yu H, Zhang Y, Leung WS, Lo IFM, Luk HM, Law WC, Ma KK, Wong CL, Wong YS, Luo R, and Lam TW
- Subjects
- Algorithms, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA, Software, Translocation, Genetic, Whole Genome Sequencing, Nanopores
- Abstract
Structural variation (SV) is a major cause of genetic disorders. In this paper, we show that low-depth (specifically, 4×) whole-genome sequencing using a single Oxford Nanopore MinION flow cell suffices to support sensitive detection of SV, particularly pathogenic SV for supporting clinical diagnosis. When using 4× ONT WGS data, existing SV calling software often fails to detect pathogenic SV, especially in the form of long deletion, terminal deletion, duplication, and unbalanced translocation. Our new SV calling software SENSV can achieve high sensitivity for all types of SV and a breakpoint precision typically ± 100 bp; both features are important for clinical concerns. The improvement achieved by SENSV stems from several new algorithms. We evaluated SENSV and other software using both real and simulated data. The former was based on 24 patient samples, each diagnosed with a genetic disorder. SENSV found the pathogenic SV in 22 out of 24 cases (all heterozygous, size from hundreds of kbp to a few Mbp), reporting breakpoints within 100 bp of the true answers. On the other hand, no existing software can detect the pathogenic SV in more than 10 out of 24 cases, even when the breakpoint requirement is relaxed to ± 2000 bp., (© 2022. The Author(s).)
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- 2022
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34. ECNano: A cost-effective workflow for target enrichment sequencing and accurate variant calling on 4800 clinically significant genes using a single MinION flowcell.
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Leung AW, Leung HC, Wong CL, Zheng ZX, Lui WW, Luk HM, Lo IF, Luo R, and Lam TW
- Subjects
- Cost-Benefit Analysis, Humans, Sequence Analysis, DNA methods, Workflow, High-Throughput Nucleotide Sequencing methods, Nanopores
- Abstract
Background: The application of long-read sequencing using the Oxford Nanopore Technologies (ONT) MinION sequencer is getting more diverse in the medical field. Having a high sequencing error of ONT and limited throughput from a single MinION flowcell, however, limits its applicability for accurate variant detection. Medical exome sequencing (MES) targets clinically significant exon regions, allowing rapid and comprehensive screening of pathogenic variants. By applying MES with MinION sequencing, the technology can achieve a more uniform capture of the target regions, shorter turnaround time, and lower sequencing cost per sample., Method: We introduced a cost-effective optimized workflow, ECNano, comprising a wet-lab protocol and bioinformatics analysis, for accurate variant detection at 4800 clinically important genes and regions using a single MinION flowcell. The ECNano wet-lab protocol was optimized to perform long-read target enrichment and ONT library preparation to stably generate high-quality MES data with adequate coverage. The subsequent variant-calling workflow, Clair-ensemble, adopted a fast RNN-based variant caller, Clair, and was optimized for target enrichment data. To evaluate its performance and practicality, ECNano was tested on both reference DNA samples and patient samples., Results: ECNano achieved deep on-target depth of coverage (DoC) at average > 100× and > 98% uniformity using one MinION flowcell. For accurate ONT variant calling, the generated reads sufficiently covered 98.9% of pathogenic positions listed in ClinVar, with 98.96% having at least 30× DoC. ECNano obtained an average read length of 1000 bp. The long reads of ECNano also covered the adjacent splice sites well, with 98.5% of positions having ≥ 30× DoC. Clair-ensemble achieved > 99% recall and accuracy for SNV calling. The whole workflow from wet-lab protocol to variant detection was completed within three days., Conclusion: We presented ECNano, an out-of-the-box workflow comprising (1) a wet-lab protocol for ONT target enrichment sequencing and (2) a downstream variant detection workflow, Clair-ensemble. The workflow is cost-effective, with a short turnaround time for high accuracy variant calling in 4800 clinically significant genes and regions using a single MinION flowcell. The long-read exon captured data has potential for further development, promoting the application of long-read sequencing in personalized disease treatment and risk prediction., (© 2022. The Author(s).)
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- 2022
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35. Extending the phenotype of DeSanto-Shinawi syndrome: A case report and literature review.
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Ho S, Luk HM, and Lo IFM
- Subjects
- Face, Humans, Muscle Hypotonia genetics, Phenotype, Intellectual Disability diagnosis, Intellectual Disability genetics, Neurodevelopmental Disorders
- Abstract
DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in the WAC gene. Affected individuals are characterized by neonatal hypotonia, developmental delay, intellectual disability, behavioral problems, and dysmorphism. Epilepsy is present in some of the patients with DESSH. By far, less than 30 affected individuals have been reported worldwide. Herein, we report a 9-year-old Chinese girl with molecularly substantiated DESSH with a de novo nonsense c. 1648C>T p.(Arg550*) variant identified in the WAC gene. Aside from developmental delay and the characteristic facial gestalt, our proband also exhibited tethered cord syndrome due to filar lipoma and left duplex kidney complicated with hydronephrosis, features not observed in any of the previously reported individuals with DESSH., (© 2021 Wiley Periodicals LLC.)
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- 2022
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36. HKG: an open genetic variant database of 205 Hong Kong cantonese exomes.
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Ou M, Leung HC, Leung AW, Luk HM, Yan B, Liu CM, Tong TM, Mok MT, Ko WM, Law WC, Lam TW, Lo IF, and Luo R
- Abstract
HKG is the first fully accessible variant database for Hong Kong Cantonese, constructed from 205 novel whole-exome sequencing data. There has long been a research gap in the understanding of the genetic architecture of southern Chinese subgroups, including Hong Kong Cantonese. HKG detected 196 325 high-quality variants with 5.93% being novel, and 25 472 variants were found to be unique in HKG compared to three Chinese populations sampled from 1000 Genomes (CHN). PCA illustrates the uniqueness of HKG in CHN, and the admixture study estimated the ancestral composition of HKG and CHN, with a gradient change from north to south, consistent with their geological distribution. ClinVar, CIViC and PharmGKB annotated 599 clinically significant variants and 360 putative loss-of-function variants, substantiating our understanding of population characteristics for future medical development. Among the novel variants, 96.57% were singleton and 6.85% were of high impact. With a good representation of Hong Kong Cantonese, we demonstrated better variant imputation using reference with the addition of HKG data, thus successfully filling the data gap in southern Chinese to facilitate the regional and global development of population genetics., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)
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- 2022
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37. CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series.
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Ho S, Tsang MH, Fung JL, Huang H, Chow CB, Cheng SS, Luk HM, Chung BH, and Lo IF
- Subjects
- China epidemiology, Familial Exudative Vitreoretinopathies, Humans, Phenotype, beta Catenin, Microcephaly genetics, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
- Abstract
CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations., (© 2021 Wiley Periodicals LLC.)
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- 2022
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38. Erratum: Erratum: KCNQ2 Encephalopathy and Responsiveness to Pyridoxal-5'-Phosphate.
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Chow CK, Luk HM, and Wong SN
- Abstract
[This corrects the article DOI: 10.1055/s-0040-1721384.]., (Thieme. All rights reserved.)
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- 2021
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39. A Fetus with Congenital Microcephaly, Microphthalmia and Cataract Was Detected with Biallelic Variants in the OCLN Gene: A Case Report.
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Ng VKS, Lau TK, Kan ASY, Chung BHY, Luk HM, Ng WF, Shi M, Choy KW, Cao Y, and Leung WC
- Abstract
Microcephaly and microphthalmia are both rare congenital abnormalities, while concurrently, these two are even rarer. The underlying etiology would be complex interplaying between heterogeneous genetic background and the environmental pathogens, particularly during critical periods of early tissue development. Here, we reported a prenatal case with microcephaly, microphthalmia, and bilateral cataracts detected by ultrasonography and confirmed by autopsy. Various routine infection-related tests and invasive genetic testing were negative. Whole genome sequencing of fetus and parents revealed OCLN gene defects may be associated with these multiple congenital abnormalities.
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- 2021
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40. Prenatal phenotype of Kabuki syndrome: A case series and literature review.
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So PL, Luk HM, Cheung KW, Hui W, Chung MY, Mak ASL, Lok WY, Yu KPT, Cheng SSW, Hau EWL, Ho S, Lam STS, and Lo IFM
- Subjects
- Case-Control Studies, Child, Child, Preschool, Female, Humans, Male, Pregnancy, Ultrasonography, Prenatal methods, Ultrasonography, Prenatal statistics & numerical data, Abnormalities, Multiple genetics, Face abnormalities, Hematologic Diseases genetics, Phenotype, Vestibular Diseases genetics
- Abstract
Objectives: Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS., Methods: We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS., Results: We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%)., Conclusions: These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping., (© 2021 John Wiley & Sons Ltd.)
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- 2021
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41. Genotype and phenotype in 18 Chinese patients with Coffin-Siris syndrome.
- Author
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Cheng SSW, Luk HM, Mok MT, Leung SS, and Lo IFM
- Subjects
- Abnormalities, Multiple physiopathology, Adolescent, Adult, Child, Child, Preschool, Face physiopathology, Female, Genotype, Hand Deformities, Congenital physiopathology, Humans, Infant, Intellectual Disability physiopathology, Male, Micrognathism physiopathology, Neck physiopathology, Phenotype, Young Adult, Abnormalities, Multiple genetics, DNA-Binding Proteins genetics, Face abnormalities, Genetic Predisposition to Disease, Hand Deformities, Congenital genetics, Intellectual Disability genetics, Micrognathism genetics, Neck abnormalities, Transcription Factors genetics
- Abstract
Coffin-Siris syndrome (CSS, MIM# 1359200) is a multisystem congenital disorder characterized by coarse facial features, hypoplasia of the fifth digits and nails, and intellectual disability. It is a genetically heterogeneous condition caused by pathogenic variants in genes encoding proteins of the BAF (BRG1-associated factors) chromatin modeling complex and its downstream transcriptional factor. To date over 220 CSS individuals with pathogenic variants found have been described in the literature. This case series reported 18 molecularly confirmed Chinese individuals (17 with ARIDIB (OMIM*614556) variants and one with SMARCB1 (OMIM*601607) variant) from 17 unrelated families in Hong Kong. The clinical features of these 18 Chinese CSS patients together with two previously reported Chinese patients with ARID1B variants were reviewed. Among the 19 Chinese patients with ARID1B variants, our data suggested a lower prevalence of feeding problem, autistic features, agenesis of corpus callosum (ACC) or partial/hypoplasia of corpus callosum, and sparse hair when compared with previous reports. There was appearing higher prevalence of digital hypoplasia. Digital hypoplasia was observed to become less noticeable with time in some patients. This report highlighted the age-dependent phenotypic presentation of CSS and ethnicity-related effect on ARID1B-CSS phenotype. Moreover, this series included the first family with molecularly confirmed maternal somatic mosaicism of ARID1B variant leading to familial CSS recurrence., (© 2021 Wiley Periodicals LLC.)
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- 2021
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42. An adult Chinese patient with developmental delay with short stature, dysmorphic features, and sparse hair (Loucks-Innes syndrome).
- Author
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Cheng SSW, Luk HM, and Lo IFM
- Subjects
- Adult, Developmental Disabilities pathology, Dwarfism, Pituitary pathology, Humans, Male, Musculoskeletal Abnormalities diagnosis, Musculoskeletal Abnormalities genetics, Musculoskeletal Abnormalities pathology, Mutation genetics, Neurodevelopmental Disorders pathology, Developmental Disabilities genetics, Dwarfism, Pituitary genetics, Minor Histocompatibility Antigens genetics, Neurodevelopmental Disorders genetics, Tumor Suppressor Proteins genetics
- Abstract
Variants of the diphthamide biosynthesis I (DPH1, OMIM*603527) are associated with developmental delay, short stature, and sparse hair syndrome (DEDSSH/DPH1 syndrome) (OMIM# 616901). Another name is Loucks-Innes syndrome. DPH1 syndrome is an ultrarare and severe neurodevelopmental disorder. Less than 20 patients were reported from different ethnicities. Here, we described the first Chinese adult with genetically confirmed DPH1 syndrome. We summarized previously reported patients in the literature and found that developmental delay, unusual skull shape, sparse hair, and facial dysmorphism were consistently present in all DPH1 syndrome patients. Dysplastic toenails and dental abnormalities are age-dependent characteristics of DPH1 syndrome. Our patient was the first reported patient with documented growth hormone deficiency. Dental and endocrine checkup should be considered in the routine follow-up of DPH1 syndrome patients., (© 2021 Wiley Periodicals LLC.)
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- 2021
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43. Evolving clinical manifestations of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome: From infancy to adulthood in a 31-year-old woman.
- Author
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Yu PT, Luk HM, Mok MT, and Lo FI
- Subjects
- Adult, DNA Polymerase III deficiency, Deafness genetics, Disease Progression, Dyslipidemias genetics, Female, Genes, Dominant, Humans, Insulin Resistance genetics, Myopia genetics, Syndrome, Telangiectasis genetics, Thinness genetics, Abnormalities, Multiple genetics, DNA Polymerase III genetics, Lipodystrophy, Congenital Generalized genetics, Micrognathism genetics, Progeria genetics
- Abstract
Mandibular hypoplasia, deafness, progeroid feature, and lipodystrophy syndrome (MDPL, MIM# 615381) is an extremely rare and recently recognized early adult onset of progeroid syndrome, with features of generalized lipodystrophy, dysmorphic features, telangiectasia, early onset hearing loss, insulin resistance, and dyslipidemia. Here, we present a 31-year-old Chinese woman with MDPL, harboring the recurrent pathogenic variant p.(Ser605del) in POLD1, illustrating the evolving manifestations of this premature aging disorder from infancy to adulthood., (© 2020 Wiley Periodicals LLC.)
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- 2021
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44. Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong.
- Author
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So PL, Luk HM, Yu KPT, Cheng SSW, Hau EWL, Ho SKL, Lam STS, and Lo IFM
- Subjects
- Abnormalities, Multiple epidemiology, Abnormalities, Multiple genetics, Adolescent, Adult, Child, Child, Preschool, Face pathology, Female, Follow-Up Studies, Hematologic Diseases epidemiology, Hematologic Diseases genetics, Hong Kong epidemiology, Humans, Infant, Infant, Newborn, Male, Phenotype, Prognosis, Vestibular Diseases epidemiology, Vestibular Diseases genetics, Young Adult, Abnormalities, Multiple pathology, Asian People genetics, DNA-Binding Proteins genetics, Face abnormalities, Hematologic Diseases pathology, Histone Demethylases genetics, Mutation, Neoplasm Proteins genetics, Vestibular Diseases pathology
- Abstract
Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature., (© 2020 Wiley Periodicals LLC.)
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- 2021
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45. Prenatal and postnatal diagnosis of Schuurs-Hoeijmakers syndrome: Case series and review of the literature.
- Author
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Seto MT, Bertoli-Avella AM, Cheung KW, Chan KY, Yeung KS, Fung JL, Beetz C, Bauer P, Luk HM, Lo IF, Lee CP, Chung BH, and Kan AS
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple pathology, Child, Developmental Disabilities diagnosis, Developmental Disabilities pathology, Female, Heterozygote, Humans, Intellectual Disability diagnosis, Intellectual Disability pathology, Male, Phenotype, Prenatal Diagnosis methods, Exome Sequencing, Abnormalities, Multiple genetics, Developmental Disabilities genetics, Intellectual Disability genetics, Vesicular Transport Proteins genetics
- Abstract
Schuurs-Hoeijmakers syndrome (SHS) is a rare syndrome involving a de novo variant in the PACS1 gene on chromosome 11q13. There are 36 individuals published in the literature so far, mostly diagnosed postnatally (34/36) after recognizing the typical facial features co-occurring with developmental delay, intellectual disability, and multiple malformations. Herein, we present one prenatal and 15 postnatal cases with the recurrent heterozygous pathogenic variant NM_018026.3:c.607C>T p.(Arg203Trp) in the PACS1 gene detected by exome sequencing. These 16 cases were identified by mining Centogene and the Hong Kong clinical genetic service databases. Collectively, the 49 postnatally diagnosed individuals present with typical facial features and developmental delay, while the three prenatally diagnosed individuals present with multiple congenital anomalies. In the current study, the use of exome sequencing as an unbiased diagnostic tool aided the diagnosis of SHS (pre- and postnatally). The identification of additional cases with SHS add to the current understanding of the clinical phenotype associated with pathogenic PACS1 variants. Databases combining clinical and genetic information are helpful for the study of rare diseases., (© 2020 Wiley Periodicals LLC.)
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- 2021
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46. Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.
- Author
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Cheng SSW, Chan PKJ, Luk HM, Mok MT, and Lo IFM
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple epidemiology, Abnormalities, Multiple physiopathology, Adult, China epidemiology, Dwarfism diagnosis, Dwarfism epidemiology, Dwarfism physiopathology, Eye Abnormalities diagnosis, Eye Abnormalities epidemiology, Eye Abnormalities physiopathology, Female, Humans, Hyperostosis, Cortical, Congenital diagnosis, Hyperostosis, Cortical, Congenital epidemiology, Hyperostosis, Cortical, Congenital physiopathology, Hypocalcemia diagnosis, Hypocalcemia epidemiology, Hypocalcemia physiopathology, Male, Middle Aged, Phenotype, Twins genetics, Abnormalities, Multiple genetics, Dwarfism genetics, Eye Abnormalities genetics, Hyperostosis, Cortical, Congenital genetics, Hypocalcemia genetics, Receptors, Virus genetics
- Abstract
Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended., (© 2020 Wiley Periodicals LLC.)
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- 2021
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47. Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions.
- Author
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Yu KP, Luk HM, Fung JLF, Chung BH, and Lo IF
- Subjects
- Adult, Child, Preschool, Craniofacial Abnormalities pathology, Developmental Disabilities pathology, Female, Humans, Infant, Intellectual Disability pathology, Male, Syndrome, Craniofacial Abnormalities genetics, Developmental Disabilities genetics, Intellectual Disability genetics, Loss of Function Mutation, Phenotype, Transcription Factors genetics
- Abstract
Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
48. Rubinstein-Taybi syndrome in Chinese population with four novel mutations.
- Author
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Yu PT, Luk HM, and Lo IFM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, China epidemiology, Female, Frameshift Mutation genetics, Humans, Infant, Male, Middle Aged, Mutation, Missense genetics, Phenotype, Rubinstein-Taybi Syndrome epidemiology, Rubinstein-Taybi Syndrome pathology, Young Adult, CREB-Binding Protein genetics, E1A-Associated p300 Protein genetics, Genetic Predisposition to Disease, Rubinstein-Taybi Syndrome genetics
- Abstract
Rubinstein-Taybi syndrome (RSTS, OMIM*180849) is a rare autosomal dominant disorder, characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, with occasional congenital anomalies. Characteristic facial dysmorphic features include downslanting palpebral fissures, low hanging columella. RSTS is caused by pathogenic variants in two ubiquitously expressed and highly homologous genes, CREBBP (OMIM*600140) and EP300 (OMIM*600140). Clinical features were well reported especially in Caucasian ethnicity. We would like to report the clinical phenotype of RSTS in our Chinese population and highlight four novel mutations in CREBBP gene., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
49. KCNQ2 Encephalopathy and Responsiveness to Pyridoxal-5'-Phosphate.
- Author
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Chow CK, Luk HM, and Wong SN
- Abstract
KCNQ2 mutations encompass a wide range of phenotypes, ranging from benign familial neonatal seizure to a clinical spectrum of early-onset epileptic encephalopathy that occurs in the early neonatal period. We report an infant with KCNQ2 encephalopathy presenting as neonatal seizure, initially controlled by two anticonvulsants. Electroencephalogram (EEG) showed repetitive multifocal epileptiform discharges, which remained similar after administration of intravenous pyridoxine injection. Seizure recurred at the age of 3 months preceded by an episode of minor viral infection, which occurred multiple times per day. No significant change in seizure frequency was observed after 5-day oral pyridoxine trial, but subsequently, there was dramatic seizure improvement with oral pyridoxal-5'-phosphate (PLP). We hope to alert clinicians that in patients with neonatal epileptic encephalopathy, particularly with known KCNQ2 mutations, intravenous injection of pyridoxine (preferably with EEG monitoring), followed by both oral trial of pyridoxine and PLP should be considered. KCNQ2 mutations should also be considered in vitamin B6-responsive patients., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
50. Rubinstein-Taybi syndrome in diverse populations.
- Author
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Tekendo-Ngongang C, Owosela B, Fleischer N, Addissie YA, Malonga B, Badoe E, Gupta N, Moresco A, Huckstadt V, Ashaat EA, Hussen DF, Luk HM, Lo IFM, Hon-Yin Chung B, Fung JLF, Moretti-Ferreira D, Batista LC, Lotz-Esquivel S, Saborio-Rocafort M, Badilla-Porras R, Penon Portmann M, Jones KL, Abdul-Rahman OA, Uwineza A, Prijoles EJ, Ifeorah IK, Llamos Paneque A, Sirisena ND, Dowsett L, Lee S, Cappuccio G, Kitchin CS, Diaz-Kuan A, Thong MK, Obregon MG, Mutesa L, Dissanayake VHW, El Ruby MO, Brunetti-Pierri N, Ekure EN, Stevenson RE, Muenke M, and Kruszka P
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Infant, International Agencies, Male, Middle Aged, Prognosis, Rubinstein-Taybi Syndrome genetics, Rubinstein-Taybi Syndrome pathology, Young Adult, E1A-Associated p300 Protein genetics, Ethnicity genetics, Face abnormalities, Genetics, Population, Mutation, Rubinstein-Taybi Syndrome epidemiology
- Abstract
Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
- Full Text
- View/download PDF
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