Detection of de novo genetic variants in Mayer–Rokitansky–Küster–Hauser syndrome by whole genome sequencing

Pan, Hongxin; Luo, Guangnan; Wan, Shengqing; Qin, Chenglu; Tang, Jie; Zhang, Meng; Du, Min; Xu, Ke; Shi, Jin-qiu

doi:10.1016/j.eurox.2019.100089

Cited by 15 publications

(16 citation statements)

References 42 publications

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“…During the last decade, the increasing availability of massively parallel sequencing technologies (also referred to as Next-Generation Sequencing, NGS) has provided new optimism in the search for genes implicated in MRKH syndrome. Recently, Pan et al performed whole-genome sequencing (WGS) analysis of nine MRKH syndrome trios (patient and both parents) demonstrating the capacity of WGS in unbiased detection of de novo genomic variation [77]. Other recent studies also used NGS technology in genomic searches for genetic variation [24,64,78,79].…”

Section: Embryology Etiology and Geneticsmentioning

confidence: 99%

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

Herlin

Petersen

Brännström³

2020

Orphanet J Rare Dis

171

160

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Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian aplasia, is a congenital disorder characterized by aplasia of the uterus and upper part of the vagina in females with normal secondary sex characteristics and a normal female karyotype (46,XX). Main body: The diagnosis is often made during adolescence following investigations for primary amenorrhea and has an estimated prevalence of 1 in 5000 live female births. MRKH syndrome is classified as type I (isolated uterovaginal aplasia) or type II (associated with extragenital manifestations). Extragenital anomalies typically include renal, skeletal, ear, or cardiac malformations. The etiology of MRKH syndrome still remains elusive, however increasing reports of familial clustering point towards genetic causes and the use of various genomic techniques has allowed the identification of promising recurrent genetic abnormalities in some patients. The psychosexual impact of having MRKH syndrome should not be underestimated and the clinical care foremost involves thorough counselling and support in careful dialogue with the patient. Vaginal agenesis therapy is available for mature patients following therapeutical counselling and education with non-invasive vaginal dilations recommended as first-line therapy or by surgery. MRKH syndrome involves absolute uterine factor infertility and until recently, the only option for the patients to achieve biological motherhood was through gestational surrogacy, which is prohibited in most countries. However, the successful clinical trial of uterus transplantation (UTx) by a Swedish team followed by the first live-birth in September, 2014 in Gothenburg, proofed the first available fertility treatment in MRKH syndrome and UTx is now being performed in other countries around the world allowing women with MRKH syndrome to carry their own child and achieve biological motherhood. Conclusion: Several advances in research across multiple disciplines have been made in the recent years and this kaleidoscopic review provides a current status of various key aspects in MRKH syndrome and provides perspectives for future research and improved clinical care.

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Section: Embryology Etiology and Geneticsmentioning

confidence: 99%

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

Herlin

Petersen

Brännström³

2020

Orphanet J Rare Dis

171

160

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“…Although the function of NBPF20 is unknown, it locates at chromosome 1q21.1, which microdeletion is associated with a variety of phenotypes including skeletal malformations such as scoliosis [35,36]. This region also contains other NBPF family members, such as NBPF10, whose genetic variants were implicated in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM # 277000) [37], a disease associated with CS [38].…”

Section: Discussionmentioning

confidence: 99%

Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis

Lai

Xin

Ming

et al. 2021

Genes

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Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5–1/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 microdeletion and TBX6 variant/haplotype causing CS in multiple cohorts, which explains about 5–10% of the affected cases. Here, we studied the genetic etiology of CS by analyzing CNVs in a cohort of 67 patients with congenital hemivertebrae and 125 family controls. We employed both candidate gene and family-based approaches to filter CNVs called from whole exome sequencing data. This identified 12 CNVs in four scoliosis-associated genes (TBX6, NOTCH2, DSCAM, and SNTG1) as well as eight recessive and 64 novel rare CNVs in 15 additional genes. Some candidates, such as DHX40, NBPF20, RASA2, and MYSM1, have been found to be associated with syndromes with scoliosis or implicated in bone/spine development. In particular, the Mysm1 mutant mouse showed spinal deformities. Our findings suggest that, in addition to the 16p11.2 microdeletion, other CNVs are potentially important in predisposing to CS.

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“…However, discordant phenotypes in monozygotic twins casts doubt on the purely genetic aetiology of MDAs ( Regenstein and Berkeley, 1991 ; Steinkampf et al, 2003 ; Duru and Laufer, 2009 ; Milsom et al, 2015 ). Both de novo and familial MDA cases have been documented, with familial ones following an autosomal-dominant inheritance pattern with reduced penetrance and variable expressivity ( Box 1 ) ( Cheroki et al, 2007 ; Devriendt et al, 1997 ; Jacquinet et al, 2020 ; Bendavid et al, 2007 ; Williams et al, 2016 ; Bernardini et al, 2009 ; Hinkes et al, 2012 ; Morcel et al, 2011 ; McGowan et al, 2015 ; Uliana et al, 2008 ; Cheroki et al, 2006 ; Rall et al, 2015 ; Ledig et al, 2018 ; Pan et al, 2019 ). These findings highlight the complex nature of MDAs and suggest a multifactorial causation and phenotypic expression.…”

Section: Technologies and Strategies To Investigate Mda Genetics And Genomicsmentioning

confidence: 99%

“…To date, a single WGS study of nine patients with MRKH type I and their respective parents has been conducted ( Pan et al, 2019 ). It identified de novo missense mutations in TNK2 , PIK3CD and SLC4A10 predicted to be deleterious and 623 de novo SNVs in non-coding regions, of which some mapped to DNase1-hypersensitive sites ( Box 1 ), transcription factor binding sites, enhancer elements and pseudogenes.…”

Section: Technologies and Strategies To Investigate Mda Genetics And Genomicsmentioning

confidence: 99%

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

González

Artibani

Ahmed

2021

Disease Models &Amp; Mechanisms

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Müllerian duct anomalies (MDAs) are developmental disorders of the Müllerian duct, the embryonic anlage of most of the female reproductive tract. The prevalence of MDAs is 6.7% in the general female population and 16.7% in women who exhibit recurrent miscarriages. Individuals affected by these anomalies suffer from high rates of infertility, first-trimester pregnancy losses, premature labour, placental retention, foetal growth retardation and foetal malpresentations. The aetiology of MDAs is complex and heterogeneous, displaying a range of clinical pictures that generally lack a direct genotype-phenotype correlation. De novo and familial cases sharing the same genomic lesions have been reported. The familial cases follow an autosomal-dominant inheritance, with reduced penetrance and variable expressivity. Furthermore, few genetic factors and molecular pathways underpinning Müllerian development and dysregulations causing MDAs have been identified. The current knowledge in this field predominantly derives from loss-of-function experiments in mouse and chicken models, as well as from human genetic association studies using traditional approaches, such as microarrays and Sanger sequencing, limiting the discovery of causal factors to few genetic entities from the coding genome. In this Review, we summarise the current state of the field, discuss limitations in the number of studies and patient samples that have stalled progress, and review how the development of new technologies provides a unique opportunity to overcome these limitations. Furthermore, we discuss how these new technologies can improve functional validation of potential causative alterations in MDAs.

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Detection of de novo genetic variants in Mayer–Rokitansky–Küster–Hauser syndrome by whole genome sequencing

Cited by 15 publications

References 42 publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update

Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

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