Rare structural variants, aneuploidies, and mosaicism in individuals with Mullerian aplasia detected by optical genome mapping

Brakta, Soumia; Hawkins, Zoe A; Sahajpal, Nikhil; Seman, Natalie; Kira, Dina; Chorich, Lynn P.; Kim, Hyung‐Goo; Xu, Hongyan; Phillips, John A.; Kolhe, Ravindra; Layman, Lawrence C.

doi:10.1007/s00439-023-02522-8

Cited by 5 publications

(9 citation statements)

References 44 publications

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“…They also reported mosaicism in three cases for trisomy 12, a 7;14 translocation, and 45,X (75%)/46,XX (25%). It was concluded that the exact mechanism for MA may be mosaicisms [ 98 ]. In another study by Brendan et al in eight individuals with MRKH, WES was used for analysis.…”

Section: Resultsmentioning

confidence: 99%

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Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review

Dube,

Kar,

Jhancy

et al. 2023

IJMS

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Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism.

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Section: Resultsmentioning

confidence: 99%

“…In a chromosomal translocation, genetic material is exchanged between two chromosomes. Translocations were detected in five different individuals involving chromosomes 8,13, 7,14, and chromosomes 3,16 [ 40 , 98 , 162 , 163 ]. These were one individual with t(8;13)(q22.1;q32.1), two with t(8;13)(q12;q14), and one with t(3;16)(p22.3;p13.3).…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review

Dube,

Kar,

Jhancy

et al. 2023

IJMS

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“…Another technology for improved analysis of structural variation is optical genome mapping, which has been applied by Brakta et al. ( 73 ). All along the technical developments, it will still be relevant to revisit sequencing data of unsolved cases, as new knowledge emerges supporting variant interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of 17q12 was first reported in MRKH syndrome by Cheroki et al. in 2008 ( 81 ) and to this date, 21 deletions have been reported ( Table 1 ) ( 30 , 71 – 73 , 75 , 76 , 81 – 86 ). Ledig et al.…”

Section: Genetic Findings In Mrkh Syndrome and Evidence For Causalitymentioning

confidence: 91%

“…Optical genome mapping is a newer cytogenomic method with higher resolution for the detection of both imbalanced and balanced structural variation and has recently been applied in a study by Brakta et al. ( 73 ). In more recent years, whole-exome and whole-genome sequencing analyses have been applied for genome-wide detection of genetic variation at the nucleotide level ( 74 , 75 , 96 – 105 ).…”

Section: Genetic Research In Mrkh Syndromementioning

confidence: 99%

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Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications

Herlin

2024

Front. Endocrinol.

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Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by agenesis/aplasia of the uterus and upper part of the vagina in females with normal external genitalia and a normal female karyotype (46,XX). Patients typically present during adolescence with complaints of primary amenorrhea where the diagnosis is established with significant implications including absolute infertility. Most often cases appear isolated with no family history of MRKH syndrome or related anomalies. However, cumulative reports of familial recurrence suggest genetic factors to be involved. Early candidate gene studies had limited success in their search for genetic causes of MRKH syndrome. More recently, genomic investigations using chromosomal microarray and genome-wide sequencing have been successful in detecting promising genetic variants associated with MRKH syndrome, including 17q12 (LHX1, HNF1B) and 16p11.2 (TBX6) deletions and sequence variations in GREB1L and PAX8, pointing towards a heterogeneous etiology with various genes involved. With uterus transplantation as an emerging fertility treatment in MRKH syndrome and increasing evidence for genetic etiologies, the need for genetic counseling concerning the recurrence risk in offspring will likely increase. This review presents the advancements in MRKH syndrome genetics from early familial occurrences and candidate gene searches to current genomic studies. Moreover, the review provides suggestions for future genetic investigations and discusses potential implications for clinical practice.

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Optical Genome Mapping for Applications in Repeat Expansion Disorders

van der Sanden,

Neveling,

Pang

et al. 2024

Current Protocols

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Short tandem repeat (STR) expansions are associated with more than 60 genetic disorders. The size and stability of these expansions correlate with the severity and age of onset of the disease. Therefore, being able to accurately detect the absolute length of STRs is important. Current diagnostic assays include laborious lab experiments, including repeat‐primed PCR and Southern blotting, that still cannot precisely determine the exact length of very long repeat expansions. Optical genome mapping (OGM) is a cost‐effective and easy‐to‐use alternative to traditional cytogenetic techniques and allows the comprehensive detection of chromosomal aberrations and structural variants >500 bp in length, including insertions, deletions, duplications, inversions, translocations, and copy number variants. Here, we provide methodological guidance for preparing samples and performing OGM as well as running the analysis pipelines and using the specific repeat expansion workflows to determine the exact repeat length of repeat expansions expanded beyond 500 bp. Together these protocols provide all details needed to analyze the length and stability of any repeat expansion with an expected repeat size difference from the expected wild‐type allele of >500 bp. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Genomic ultra‐high‐molecular‐weight DNA isolation, labeling, and stainingBasic Protocol 2: Data generation and genome mapping using the Bionano Saphyr® SystemBasic Protocol 3: Manual De Novo Assembly workflowBasic Protocol 4: Local guided assembly workflowBasic Protocol 5: EnFocus Fragile X workflowBasic Protocol 6: Molecule distance script workflow

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Rare structural variants, aneuploidies, and mosaicism in individuals with Mullerian aplasia detected by optical genome mapping

Cited by 5 publications

References 44 publications

Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review

Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review

Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications

Optical Genome Mapping for Applications in Repeat Expansion Disorders

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