A prenatal case of split-hand malformation associated with 17p13.3 triplication – A dilemma in genetic counseling

Luk, Ho‐Ming; Wong, Vincent; Lo, Ivan F.M.; Chan, Kelvin Y.K.; Lau, Elizabeth T.; Kan, Anita Sik Yau; Tang, Mónica; Tang, William; She, Wandy M.K.; Chu, Yoyo Wing Yiu; Sin, WK; Chung, Brian Hon‐Yin

doi:10.1016/j.ejmg.2013.12.005

Cited by 11 publications

(17 citation statements)

References 7 publications

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“…This study demonstrates the limitation of clinical microarrays (NimbleGen CGX‐135K array, average resolution of 140 kb across the genome and 40 kb or less in regions of clinical relevance [Luk et al., ]) in differentiating higher‐order copy‐number changes, such as triplications and quadruplications. Higher copy‐number changes (comparing triplication to duplication) are known to be associated with more severe phenotypes for certain dosage‐sensitive genes, including YWHAE and BHLHA9 [Fuchs et al., ; Bi et al., ; Liu et al., ; Nagata et al., ].…”

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confidence: 90%

“…Previously, we reported a prenatal case (BAB7218) with split‐hand malformation detected by fetal ultrasound [Luk et al., ]. Clinical microarray (NimbleGen CGX‐135K array) showed two maternally inherited triplications separated by a copy‐number neutral region at 17p13.3 in the fetus.…”

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confidence: 99%

“…The patient is now 15 months of age with normal gross motor, fine motor, and speech development at 3 and 12 months of age. The mother has a history of mild right talipes equinovarus, but she has no additional skeletal anomalies and has a normal intellect [Luk et al., ].…”

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confidence: 99%

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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Posey

Yuan

et al. 2015

Human Mutation

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Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal non-allelic homologous recombination to generate the quadruplications in this family.

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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Posey

Yuan

et al. 2015

Human Mutation

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“…Most countries and major societies already endorsed the use of CMA in place of karyotyping for prenatal diagnosis (Armour et al, ; Committee on Genetics & the Society for Maternal‐Fetal Medicine, ; Malan et al, ; RANZCOG, ; Vanakker et al, ). CMA has been commonly accepted as part of prenatal diagnosis in the last several years in Hong Kong not only to improve the prenatal care (Cheng, Kan, Hui, Lee, & Tang, ; Kan & Chan, ), but also to understand the underlying causes of the fetal abnormalities (Au et al, ; Cheung et al, ; Hui et al, ; Lau et al, ; Leung et al, ; Luk et al, ). This would not be achieved by conventional cytogenetics although CMA remained a self‐financed test.…”

Section: Introductionmentioning

confidence: 99%

Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong

Cheng

Chan

Leung

et al. 2019

American J of Med Genetics Pt C

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Chromosomal microarray (CMA) is recommended as a first tier investigation for patients with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD), and multiple congenital anomalies (MCA). It is widely used in the prenatal and postnatal settings for detection of chromosomal aberrations. This is a retrospective review of all array comparative genomic hybridization (aCGH/ array CGH) findings ascertained in two major prenatal and postnatal genetic diagnostic centers in Hong Kong from June 2012 to December 2017. Medical records were reviewed for cases with pathogenic and variants of uncertain clinical significance (VUS). Classification of copy number variants (CNVs) was based on current knowledge and experience by August 2018. The aims of this review are to study the diagnostic yield of array CGH application in prenatal and postnatal settings in Hong Kong and to describe the spectrum of abnormalities found. Prenatal indications included abnormal ultrasound findings, positive Down syndrome screening, abnormal noninvasive prenatal test results, advanced maternal age and family history of chromosomal or genetic abnormalities. Postnatal indications included unexplained DD, ID, ASD, and MCA. A total of 1,261 prenatal subjects and 3,096 postnatal patients were reviewed. The prenatal diagnostic yield of pathogenic CNV and VUS (excluding those detectable by karyotype) was 3.5%. The postnatal diagnostic yield of pathogenic CNV was 15.2%. The detection rates for well-defined microdeletion and microduplication syndromes were 4.6% in prenatal and 6.1% (1 in 16 index patients) in postnatal cases, respectively. Chromosomes 15, 16, and 22 accounted for over 21 and 25% of pathogenic CNVs detected in prenatal and postnatal cohorts, respectively. This review provides the first large scale overview of genomic imbalance of mostly Chinese patients in prenatal and postnatal settings.

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“…A multicentre study in UK on array comparative genomic hybridisation in prenatal diagnosis of fetal anomalies concluded that CMA was a robust, acceptable, and probably cost-effective method to detect more clinically significant chromosomal imbalances in anomalous fetuses 17 . In Hong Kong, CMA has been accepted as a part of prenatal diagnosis to improve the prenatal care [18][19][20][21] and to investigate the underlying causes of fetal abnormalities 7,[22][23][24][25][26][27][28][29][30][31][32][33] that cannot be achieved by conventional cytogenetics alone.…”

Section: Prenatal Diagnosis Workflow With Cmamentioning

confidence: 99%

Development of cytogenomics for prenatal diagnosis: from chromosomes to single nucleotides: a review

Chan

Kan

2019

Hong Kong Journal of Gynaecology, Obstetrics and Midwifery

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Prenatal diagnosis encompasses traditional cytogenetics and molecular-based techniques. In the new era of genomics, challenge to prenatal diagnosis has led to revised diagnostic strategies. In this review, we discuss the application of chromosomal microarray and a new prenatal diagnosis workflow in the public setting in Hong Kong. Using this prenatal diagnosis workflow, up to 40% of fetuses with structural anomalies can be identified with an underlying genetic aetiology, leaving the majority of cases undiagnosed. With the advancement of next generation sequencing, we are able to tackle the challenge of investigating chromosomal changes to single nucleotide variant level. Therefore, we also discuss whole exome sequencing, whole genome sequencing, and long-read sequencing, as well as their limitations and prenatal applications. This DNA-based technology should be evaluated for prenatal clinical application in Hong Kong.

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A prenatal case of split-hand malformation associated with 17p13.3 triplication – A dilemma in genetic counseling

Cited by 11 publications

References 7 publications

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong

Development of cytogenomics for prenatal diagnosis: from chromosomes to single nucleotides: a review

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