Müllerian Agenesis Causing Congenital Uterine Factor Infertility: Comparison
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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. 

  • Müllerian agenesis (MA)
  • uterine aplasia
  • Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome
  • uterine agenesis

1. Introduction

Infertility is defined by the World Health Organization (WHO) as a disease of the male or female reproductive system resulting in failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse [1]. It can be “Primary”, denoting those who have never become pregnant, or “Secondary”, depicting those with the inability to conceive after at least one previous pregnancy [2]. Infertility affects millions of people worldwide [3]. The prevalence of infertility can vary throughout the world, but generally affects around one in five couples [4]. Infertility can be caused by different factors in males, females, and can be combined or even unexplained [3]. Common causes in females are diseases of the ovaries, fallopian tubes, uterus, endocrinal, genital tract dysbiosis or combined, and differ from country to country [5]. Similarly, the cause can commonly be obstruction of the tract, testicular failure of spermatogenesis, poor sperm quality, or endocrinal in males [3]. Uterine factor infertility (UFI) is defined as an absent uterus (absolute UFI) or as a nonfunctional uterus (non-absolute UFI) [6]. Absolute UFI can be due to congenital absence of the uterus or due to a hysterectomy later [6]. UFI can affect about 1 in 500 women of reproductive age or up to 5% of females, although the exact data are unknown [7][8].

2. Genetic Basis of MA

A universally agreeable gene is yet to be found in the available evidence. There are elaborate investigations into candidate genes associated with MA. Out of the proposed genes, one or more were implicated in specific cohorts, but none were found in all. It is rational to propose that the genes or regulators of genes essentially involved in Müllerian duct development are most likely to be involved in MA [9]. The WNT signaling pathway genes (WNT4, WNT9B), the HOX family genes, LX1, HNF1B, and a few other candidate genes have been implicated by Mikhael et al. through WES, which was then confirmed by Sanger sequencing [10]. The copy number variants (CNVs) at different locations in chromosomes 1, 16, 17, and 22 were identified by this study [10] (Table 1). A glossary of gene names is available as supplementary material.
Table 1. Genes suspected to be involved in MRKH.
Genes and Location in Chromosome Reference Method Used Associations
MEFV and IL-32-16p13.3

CMTM7-3p22.3

CCR4 3p22.3		 [11] CGH and RT-qPCR IL32 and MEFV gene mutations associated with Mediterranean fever. MRKHS
BAZ2B and SLC4A10-2q24.2

KLHL18-3p21.31

PIK3CD-1p36.22

TNK2-3q29		 [12] WGS MRKHS
LAMC1-1q25.3

RARA-17q21.2

HOXA10-7p15.2

PAX2-10q24–25

MMP14 and

LRP10-14q11.2		 [10] WES, confirmed by Sanger sequencing MRKHS
IFTP57, HHLA2 and MYH15-3q13.13

PLA2R1-2q23-q24

ITGB6 and RBMS1-2q24.2		 [13] SNP microarray analysis MRKHS
32]

4q35.2 Deletion 1.1 Mb [26]

Mutation g79204031G>A and g.15542618C>T [14]		 1. FRAS1 (g79204031G>A) [14]

2. CC2D2A (g.15542618C>T) [14]		 LRP10-14q11.2

FRAS1-4q21.21

CC2D2A-4p15.32

KIF14-1q32.1

RSPO4-20p13

MKKS-20p12.2

NPHP3-3q22.1

DYNC2H1-11q22.3

SPECC1L-22q11

VWF-12p13.31		 [14] WES MRKHS
5 5p11 Deletion 0.40 Mb [34]

5q14.3 Deletion 0.40 Mb [34]		   TBC1D1-4p14

KMT2D-12q13.12

HOXD3-2q31-37

DLG5-10q22.3

GLI3-7p14.1

HIRA-22q11.21

GATA3-10p14

LIFR-5p13.1

CLIP1-12q24.31		 [15] Sanger sequencing MRKHS
6 6p21 Duplication 0.17 Mb [32]

6q25.1 Duplication 0.42 Mb [32]

6q25.2 Duplication 0.44 Mb [32]

6q11.1 Duplication 0.41 Mb [34]		   PRKX-Xp22.33

HOXC8-12q13.13		 [16]
7 7p15.2 Hypomethylation [124]RT-qPCR

7p14 Duplication 1.75 Mb [32]

MRKHS, Urinary malformations, skeletal malformations, and/or hearing defects.
7q31.2 Deletion 1.8 Mb [26]

Mutation g111503593C>T [14]		 1. HOXA5 is a transcriptional regulator of p53 and progesterone receptor (PGR). Hypomethylation leads to overexpression, which causes overexpression of PGR [125]. Ectopic HOXA5 expression at the 5′end of the cluster might prevent normal differentiation of the MD or even regression.

2. It most likely involves Abdominal B (AbdB) homeobox genes (HOX-A9, A10, A11, and A13), required for differentiation and segmental patterning of MD [126]

3. HOXA9 is expressed in the region that becomes the oviduct [127]. Ectopic expression of HOXA5 or HOXA9 inhibits MD differentiation [128].

4. DOCK4		 MUC1-1q22 [16][17]
8 8p23.1 Hypomethylation [57]

8p23.1 Activating mutations 		Array analysis, RT-qPCR [124MRKHS
] GATA binding protein 4 promotes AMH production and regulates sex determination and differentiation [57]. Overproduction of AMH leads to MA. RBM8A-1q21 [18][19][20][21][22] Array CGH, MLPA TAR syndrome (thrombocytopenia, absence of radius) [18
10 10q24 Duplication 0.05 Mb [32]][19][20  ][21]
WNT9B-17q21 [9][10][21][23][24
11 11p11.12 Deletion 0.76 Mb (45)

11p 13 Hypomethylation [57]]

11p 13 Activating mutation [124][25]

Mutation g.102985987C>T [14][26]		 Array CGH, WES MA, renal abnormalities, and cervicothoracic somite dysplasia [9]
1. WT1 is a regulatory factor important for the transcription of anti-Müllerian hormone (AMH) genes. It promotes AMH expression and regulates sex determination and differentiation [57]. Activating the mutation of the gene for the AMH receptor, or the receptor, causes excessive production of AMH, leading to MRKHS [124]

2. DYNC2H1		 TBX6-16p11.2 [9][10
12 12q13.13 Duplication [13]][14][20][21][22][27][28][29][30][31] Array CGH. WES

12q23 Duplication 0.16 Mb [32]

12q24 Duplication 0.12 Mb [32]Autism spectrum disorders, neurological disorders, unaffected persons [21]


Mutation g.6085324G>A [14 ACTR3B-Pseudogenes chromosomes 2, 4, 10, 16, 22 and Y [25] WES MA
] VWF
13 13q21 Deletion 0.41 Mb [26]   LHX1-17q12 [18][19][21][26][27][28][32][33][34][35][36][37][38][39][40]
14 14q32.33 Deletion 0.46 Mb [Array CGH, gene sequencing 34]

14q32.33 mutation g.23345412G>A [14]MA, Anomalies in the body axis formation [21], diabetes [33], learning disability [33]
LRP10 TCF2/HNF1B-17q12
15[18] 15q21.1 Deletion 0.28 Mb [34][19][27][28

15q26.3 Deletion 0.54 Mb [26]][32][33][34][35][36][37][38][39][41][42]

Array CGH, DNA sequencing		 Deletions at 15q11.2 [119]MA, Renal cysts [21] diabetes [21][33  ], learning disability [33]
TBX1-22q11 [18][19][20][27]
16 16p13.3 Increased expression [11][43][44][45][46]

16q11.2 Duplication 0.20 Mb [Array CGH, FISH, MLPA		 27]

16p11.2 Deletion (size 0.55 Mb to 0.6 Mb) [27]

Splice site mutation c.622-2A>T (g.30100162 T>A) [28]

Mutation c.484G>A(rs56098093) p.Gly162Ser [28]

Mutation c.815G>A p.Arg272Gln [28]

Mutation c.815G>A [26]		 1. Genes for IL32 and MEFV.

DiGeorge syndrome, heart defect, hypocalcemia, immunodeficiency, typical facial malformations, cognitive and behavioral disorders
2. TBX6 is involved in paraxial mesoderm formation and somitogenesis in human embryos [129]. Deletion induces MRKHS due to the loss of the transcription factor. WNT4-1p36.12 [
1710][ 17q12 Deletion (size 1.2 to 1.9 Mb) [13]38][18][47][19][48][20[49] ][27][32][34]

17q12 Missense mutation of LHX1 [18][33]

c.790C>G p.(Arg264Gly)PCR sequencing, CGH

c. c.25dup p.(Arg9Lysfs*25)

17q21-22 mutations

c.28G>T p.Ala10Ser

c.205C>T, p.Arg69Trp [25]

c.*158C>THyperandrogenism (Atypical MRKHS), Gonadal dysgenesis


17q21-22 Five Missense mutations [26]

c.472C>G p.(Gln158Glu)

c.665G>A p.(Arg222His)

c.722G>A p.(Arg24His)

c.974G>A p.(Arg325His)

c.1029C>A p.(Cys343*)		 1. Involves the LHX1(LIM homeobox protein 1) gene, which is a transcription factor necessary for the formation of the Müllerian duct-derived uterine and vaginal epithelia [92].

2. HNF1B is [Pit–Oct–Unc homeodomain-containing transcription factor that is frequently expressed in the Müllerian duct during development [130]. It positively regulates the expression of LHX1, PAX2, and WNT9B [131].

3. Involves mutations in WNT9B, which acts upstream of another Wnt4. It is responsible for the caudal extension of the Müllerian duct and the organization of the urogenital system [98].		 GREB1L-18q11.1-q11.2 [16][25][50][51]
18 18q23 Duplication 0.20 Mb [34][52] WES, CGH

18p Deletion [132MRKHS type 2 with kidney abnormalities, Twins discordant for MRKHS [16]
]

18q11.1-q11.2 mutation c.4665T>A, p.Tyr1555		 GREB1L is a target gene in the retinoic acid signaling pathway, which is highly expressed in the developing fetal human kidney and involved in the early metanephros and genital development [133]. DOCK4-7q31.1
19[14] 19q13.31 deletion [119][35]   OR2T2 MRKHS
ZNF277-7q31.1 [35]   MRKHS
DACT1-14q23.1 [53]   MRKHS
DLGH1-3q29 [54] Direct sequencing Unilateral agenesis, pelvic kidney
OXTR-3p25.3 [55] DNA sequence analysis MRKHS
ESR1-6q25 [56] DNA sequence analysis MRKHS
WT1-11p13 [57] PCR  
GATA4-8p23.1 [57] PCR  
EMX2-10q26 [9][58][59] Sequence analysis MRKHS, other Müllerian fusion abnormalities
SHOX-Pseudoautosomal region Xp22. 3 [10][60][61] CGH MRKHS
PBX1-1q23.3 [62]   MRKHS
PAX8-2q14.1 [9][25][60][63] Array CGH. WES Mutations have been associated with thyroid dysgenesis, thyroid follicular carcinomas, and atypical follicular thyroid adenomas [64], MRKHS
CGH = Comparative genomic hybridization; MLPA = Multiplex ligation-dependent probe amplification; WES = Whole-genome exon sequencing; WGS = Whole-genome sequencing; RT-qPCR = Reverse-transcriptase quantitative polymerase chain reaction; MA = Müllerian agenesis.
To overcome the drawbacks of WES, WGS was used recently by Pan et al. In addition, to further strengthen the prior evidence on specific gene involvements, this study identified five de novo variants in nine patients with MA [12]. There are also certain case reports of the involvement of CFTR, β-catenin, and te HOXA10 gene in women with complete uterine aplasia. However, it was concluded that it is unlikely to be the causative factor [65][66][67]. In a recent study by Ragitha et al. using PCR sequencing of coding exons of the WNT4 gene in 32 women with MA and gonadal dysgenesis, single-nucleotide variations, nucleotide substitution in intronic regions not affecting the normal splicing mechanism, and synonymous polymorphism (c.861C > T; p.G287G, rs544988174) were reported. Hence, any indication of WNT4 involvement in MA was not found [48]. There are a few studies exploring the inheritance of MA in families. It was not conclusively found to have a particular inheritance pattern, although an autosomal dominant trait was suggested in a few and refuted in others [42][52][68][69][70]. The challenges were incomplete family tree availability or of a particular genetic basis. Analyzing the specific genetic composition of monozygotic twins is very helpful in the identification of genetic contributions to the pathophysiology of diseases. When a single embryo divides into two after fertilization, the resultant pregnancy is called a monozygotic twin pregnancy. As they have developed from a single embryo, it is assumed that they share identical genetic composition. Studying the genetic pattern of monozygotic twins where only one has a condition gives us an insight into additional causative factors responsible for occurrences like de novo dominant mutations, or somatic mutations in the specific tissue. In a recent study on five pairs of monozygotic twins discordant for MA, the uterine tissue remnants and blood were studied using WGS [25]. They reported a mosaic variant in ACTR3B. This variant was absent in the blood of the normal twin, had low and high allele frequency in the blood, and affected tissue of the twin with MA, respectively [25]. Few of the studies elaborated on transcriptome analysis of endometrial samples from the rudimentary tissues. In a previous study of 35 sporadic patients with MRKH, perturbations in endometrial transcriptomes were described [70] This study in uterine remnants using RNA sequencing demonstrated a large number of upregulated (1236 in MRKH type 1 and 801 in MRKH type 2) and downregulated (670 in MRKH type 1 and 373 in MRKH type 2) genes associated with MRKHS [71]. It was also found that genes encoding for estrogen receptor 1 were perturbed in a few other studies [55][56][72]. Analysis of endometrial tissue in monozygotic twins also showed similar perturbations in a recent study by Buchert et al. [25]. In a recent study by Brakta et al. 2023, genetic analysis using optical genome mapping in 87 women with MRKH and available parents revealed 14 structural variants in 17/87 (19.5%). These included deletions (n = 7), duplications (n = 3), one new translocation t(7;14)(q32;q32) (n = 5), a previously identified translocation-t(3;16)(p22.3;p13.3), and aneuploidies (n = 2). 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 [73]. In another study by Brendan et al. in eight individuals with MRKH, WES was used for analysis. The study reported multiple damaging and potentially damaging changes in more than one woman involving chromosomes 1, 3, 4, 7, 8, 11, 12, 20, and 22 [14]. Furthermore, few of the studies have reported no abnormality in the homeobox gene, the PAX2, WNT4, GALT, AMH, and AMHR genes, copy number changes, and AMH promotor sequence variations [74][75][76][77][78][79][80][81][82][83][84][85]. Another interesting study has reported a testis-specific protein 1-Y-linked (TSPY) gene in two women out of six with MRKHS and the 46XX karyotype [86]. Similarly, the level of galactose-1-phosphate uridyl transferase (GALT) was found to be lower in erythrocytes of women with vaginal agenesis, and two variants of the GALT gene were detected in another study [87]. This suggests that multiple genes and multiple mechanisms may be involved in the pathogenesis of MA.

3. Mechanisms of Genetic Changes

The development of female genital organs is a complex process and is influenced by the interplay of genetic, hormonal, and environmental factors. To understand the basis of genetic abnormalities resulting in MA, a brief overview of the development of MDs is essential. During embryonic development, in both male and female fetuses, the gonadal ridges have the capacity to form either the testis or ovary until 6 weeks after conception. In the gonadal ridges, the supporting-cell lineage derived from the multipotent somatic progenitor cells is programmed to include pre-granulosa (WNT4, RSPO1, FST, and CTNNB1) genes in XX fetuses [88][89]. Müllerian (paramesonephric) ducts that give rise to most of the female reproductive tract arise around 5–6 weeks of gestation as a cleft lined by the coelomic epithelium in the urogenital ridge. Further development occurs in phases [90][91]. At first, there is a thickening of the coelomic epithelium along with expression of LHX1, and anti-Müllerian hormone receptor type II (AMHR2) [90][92][93][94]. DACH1 and DACH2 are transcriptional co-factors that act by regulating the expression of LHX1 and WNT7A and are required for the formation of MD [95][96]. In the next phase, these primordial Müllerian cells invaginate from the coelomic epithelium to reach the Wolffian duct. WNT4 expression in the mesonephric mesenchyme is essential for the Müllerian duct progenitor cells to begin invagination [92][97]. The last is the elongation phase, which begins when the invaginating tip of the Müllerian duct contacts the Wolffian duct. There is then proliferation and caudal migration of cells. There is continued elongation of MD, which eventually fuses centrally close to the urogenital sinus. MD then establishes apico-basal characteristics and develops into an epithelial tube that gives rise to the endometrium, and the surrounding mesenchyme differentiates into the myometrium of the uterus and Fallopian tubes [90][94]. The Wolffian duct plays an important role in the growth of MD, by supplying WNT9B secretion [98]. LIM1 or PAX2 are transcription factors contributing to MD growth. SOX9 has an important role in the regression of the MDs. In male fetuses, the SRY (sex-determining region on the Y) gene encodes the transcription factor SOX9, which plays a vital role in gonadal differentiation. Upregulation of the expression of SOX9 in normal male development causes the development of Wolffian duct and degeneration of MDs upregulating the expression of anti-Müllerian hormone (AMH), and results in the downregulation of WNT4 expression [99][100][101][102][103][104]. Other members of the SOX family and various other factors act through upregulation or downregulation of SOX9 to control MD development. SOX3 can induce SOX9 expression, and SOX8 and SOX10 upregulate SOX9 expression [105]. Similarly, Foxl2 downregulates SOX9, and targeted disruption of Foxl2 leads to SOX9 upregulation in the XX gonad [106]. Prostaglandin D2 also upregulates SOX9 in the absence of SRY [107]. The role of WNT4 is crucial in the development of the internal genital tract. WNT4 is a secreted protein that functions as a paracrine factor to regulate several developmental mechanisms including the uterus, cervix, and fallopian tubes. In fetuses with XX chromosomes, the absence of SRY releases WNT4 expression, which stabilizes β-catenin and silences SOX9 [108]. β-catenin is responsible for oviduct coiling [109][110]. Many growth factors, such as LIM1, EMX2, HOXA13, PAX2 and 8, and VANGL2 are also essential for the development of reproductive organs. RSPO1 is expressed in the undifferentiated gonadal ridge of XY and XX embryos and increases in the XX gonads in the absence of SRY. RSPO1 binds to G protein-coupled receptors, stimulates the expression of WNT4, and cooperates with it to increase cytoplasmic β-catenin. The increase inWNT4/β-catenin counteracts SOX9, thus leading to the ovarian pathway [111]. There are various genetic mechanisms that are potentially involved in causing a disorder, which can occur in isolation or in combinations to result in a condition. Human genomes are dynamic entities constantly influenced by alterations. The cumulative effects of small-scale sequence alterations (caused by mutation) and larger-scale rearrangements can bring about changes in the genome over a period of time [112]. The genome contains coding regions and non-coding regions. The coding regions of the DNA are directly involved in the formation of proteins, and noncoding regions may or may not be involved in the regulation of gene expression. Regulation of gene expression occurs thanks to long non-coding RNAs and epigenetic, transcriptional, post-transcriptional, translational, and protein location effects [113]. The genes that encode for an important protein related to a particular disease or a physical attribute are called candidate genes [114]. When there are chromosomal deletions, especially of the area encoding for a specific gene, the genetic functions can be completely lost, and resulting phenotypes can be severe [115][116]. Candidate genes for MA are thus thought to be related to the development of the Müllerian or Wolffian duct, or related to regulatory factors like anti-Müllerian hormone (AMH), estrogen, and estrogen receptor. The candidate genes identified by different studies are WNT4, LHX1, HNF1B, and HOXA10 [33][37][42][47][49][92][117][118]. Other genes with possible causative roles not yet substantiated adequately are HNRNPCL1, ITIH5, LRP10, MMRP14, OR2T2, OR4M2, PAX8, PDE11A, RBM8A, SHOX, TBX6, WNT9B, and ZNF816 (Table 1). A careful balance of levels of different proteins significantly influences the embryonic developmental processes. Duplications of genes encoding these proteins can result in extra gene copies, and the resulting alteration of gene dosing can lead to developmental defects [116]. A proposed mechanism for MA is an overdose of AMH. Duplications were found in many reported studies in multiple locations involving chromosomes 1,2,3,6,7,10,12,16,18,22 and X chromosomes (Table 2). However, the exact mechanisms of how these changes are related to the causation of MA are yet to be verified.
Table 2. Mechanisms of genetic changes.
Chromosome Number Mechanism [Reference] Possible Gene Involved
1 1q31.1 Duplication (size 0.4 Mb) [27]

1q44 Deletion (size 0.32 Mb) [20][119]

1p36.12 mutations

1p36.21 deletion [119]

Mutation p.(Glu226Gly) [49]

Mutation c.1026C>T [45]

Mutation p.(Arg83Cys) [120]

Mutation c.35C>T p.(Leu12Pro) [121]

Mutation c.483C>T [122]

Mutation c.697G>A p.(Ala233Thr) [47]

Mutation g.200583493A>T [14]

1q21 Deletion (size 0.4 Mb to 4.6 Mb) [18][20][119]

1q21 Duplication (size 0.26 Mb to 0.36 Mb) [19][20]		 1. KIF14 [14]

2. WNT4 is responsible for sex determination and affects the invagination of coelomic epithelial cells [97].

WNT4 mutation inhibits repression of ovarian steroid enzymes and causes abnormal expression of 17α hydroxylase and hyperandrogenism [47]

3. OR4M2, ZNF816 and PDE11A [119]
2 2p14 Duplication (size-0.23 Mb) [18]

2p14 Mutation c.1315G>A, p.Ala439Thr [25]

2p23.1 Duplication (size-0.21 Mb) [27]

2p24 Deletion (size-4.6 Mb) [27]

2q11.2 Duplication (size-1.3 Mb) [27]

2q24.2 Duplication [13]

2q13 Deletion (size-0.12 Mb) [18]		 1. The PAX8 gene encodes a homeodomain signaling molecule, strongly expressed in the MD [123].

2. Duplication at 2q24.2 of proband MRKHS involved PLA2R1, ITGB6 and RBMS1
3 3p21 Duplication 0.10 Mb [32]

3p21 Mutation c.861G>A [122]

3q13 Duplication at 3q13. [13]

3q29 Deletion 0.05 Mb [32]

Mutation g.132403615G>A [14]		 1. WNT7A encodes secreted signaling proteins, and is involved in the development of the anterior–posterior axis in the female reproductive tract. Coded proteins are responsible for patterning during embryogenesis. Their role in MA is uncertain.

2. May involve DLGH1, OXTR, NPHP3
4 4q28 Deletion 0.11 Mb [32]

4q32 Deletion 0.34 Mb [
[
119
]
20
20q13.12 Deletion


Mutations g.941074G>A and g.10393439C>A
[
14
]
1. WISP2 is significant in smooth muscle cell proliferation and migration, and is induced by estrogen in the uterus [134]. Estrogen regulates AMH expression levels [135], and overexposure to estrogen during development activates AMH promotors [124].

2. RSPO4

3. MKKS
22 22q11 Deletion (size 0.39 Mb to 2.6 Mb) [27][33][43][45]

Duplication (0.6 Mb–3.5 Mb) [19][33][136]

Mutations g.24720297G>A and g.24718408G>A [14]		 1. TBX1

2. SPECC1L
X Xp11.1 Deletion 0.12 Mb [32]

Xp11.3 Duplication 0.24 Mb [32]

Xp22 Duplication (0.07 to 0.36) [16][18][19][20][137]

Xq21.31 Deletion 1 Mb [138]

Xq deletion [139]

Xq22.3 Duplication 0.09 Mb [32]

Xq22.3 Microdeletion at Xp22.33 [13]		 1. May involve the PRKX gene, encoding for a serine/threonine kinase implicated in renal epithelium morphogenesis [16].

2. May involve the SHOX gene, which encodes a transcription factor responsible for skeletal growth. The exact mechanism is unknown.
8,13 t(8;13) (q12;q14) translocation Translocation causes MRKHSS with or without renal hypoplasia [140].
t(8;13)(q22.1;q32.1) translocation Translocation causes MRKHS with limb, breast, and urinary functional defects [141]
3,16 t(3;16) (p22.3;p13.3) translocation Translocation causes MRKHS [11][73]
7,14 t(7;14)(q32;q32) translocation Translocation seen in MRKHS [73]
2, 4, 10, 16, 22 and Y c.1066G>A, p.Gly356Arg [25] ACTR3B encodes a member of the actin-related proteins and plays a role in the organization of the actin cytoskeleton [142]. ACTR3B can have pseudogenes in more than one chromosome.
A glossary of the genes can be found in the supplementary materials; MD = Müllerian duct.
Mutations involve changes in the nucleotide sequence of a short region of a genome. The number of mutations occurring is usually minimized by the inherent DNA-repair enzymes in the cell, and mutations persist only when the cellular DNA-repair mechanisms fail. The mutations on coding regions are of various types. A lot of mutations are point mutations, where one nucleotide is replaced with the other, or it can involve the insertion or deletion of one or a few nucleotides [112]. Insertions of small numbers of extra nucleotides in the polynucleotide being synthesized, or failure of some nucleotides in the frame being copied, can alter the entire sequence/codon down the frame. Such proteins are usually markedly different from the original proteins. This is called a frame-shift mutation. Silent mutations (also called synchronous) are said to have occurred when changes in the nucleotide sequence have no effect on the functioning of the genome and they do not change the encoded amino acid [143]. Missense mutations are changes that alter a codon to another one, meaning the resultant amino acid is a completely different one. The effects of missense mutations are difficult to predict. If the resultant amino acid is similar to the original one or the change is in a non-critical amino acid, the functions are retained. However, the mutant protein may have a completely different function if the change affects a critical amino acid or the new amino acid is not similar to the original. On the other hand, if the mutation results in the stopping of the translation of the mRNA prematurely because of a stop codon, this is called a nonsense mutation. Nonsense mutation results in a shortened protein, which can be non-functional and this effect depends on how much of the polypeptide is lost [143]. There are various types of mutations documented in the literature, including point mutations, frameshift mutations, and missense mutations in patients with MA (Table 2). While some of these changes involve candidate genes directly, the significance of others is unclear. It is also noteworthy that DNA methylation levels act as a regulator of gene expression. The presence of DNA methylation, in general, prevents transcriptional activation of genes at a specific cell type [144][145]. A search for altered imprinting markers at the 11p15 imprinting control region 1 (ICR1) in 100 patients with MRKHS failed to detect any defects at that locus [146]. However, it did not rule out the possibility of imprinting alterations at other locations in the etiology of MRKHS. 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 [11][73][140][141]. 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). In the latest case report of these by Williams et al., about ten potential genes were identified, and four of significance were further substantiated [38]. As none of the family members in the cases had similar translocations, these were regarded as sporadic occurrences.

4. Fertility Options in Women with Müllerian Agenesis

MA means absolute infertility in females, and the diagnosis can be associated with considerable psychological trauma [147]. Hence, the management requires a multidisciplinary approach including gynecologists, fertility specialists, psychologists, clinical nurse specialists, support groups, and counselors [148]. Options for parenthood in these women include surrogacy and uterine transplantation if parents seek a biologically related baby. Adoption is an option if a biologically related baby is not desired in the first place or the options have failed, are unacceptable, or contraindicated [147]. Gestational surrogacy is a popular option in women with AUFI, especially with functioning ovaries, as in MA. The oocytes of the women with MA are collected and fused with the partner’s spermatozoa through in-vitro fertilization. The resulting embryo is then transferred to the uterus of the gestational surrogate. The couple then legally adopts the child from the mother after birth. Legal parenthood of a biologically related child is thus achieved [149]. The woman carrying the pregnancy is called a gestational surrogate. The surrogate can be a close relative of the couple (altruistic) or unrelated, which would be a commercial surrogate. A study by Petrozza et al. did not find evidence of inheritance or congenital anomalies in babies born through surrogacy [70]. However, there are legal implications for this method, which can vary in different countries. Surrogacy as such or specific surrogacy may not be legally permitted in specific countries due to sociocultural issues [147][150][151]. Countries can have different policies regarding commercial or altruistic surrogacy [152][153]. In the United Kingdom, surrogacy is permitted, but surrogacy agreements are not legally enforceable. The surrogate remains the child’s legal mother from birth, up until the parenthood is legally transferred to the intended parents. This is generally carried out after 6 weeks of birth. In case of disputes, the surrogacy arrangement is not legally enforceable [147]. Uterine transplant (UT) involves transplantation of the uterus with the cervix, ligamentous supports, and blood vessels. This results in restoring the natural anatomy. Successful pregnancy and childbirth after a UT ensure conditions akin to natural biological parenthood, which is acceptable both legally and socially. The first live birth following UT was reported in Sweden in 2014 [154]. Since then, numerous case reports and series have been published. A recent review has reported 18 live births out of 45 cases of UT [155]. Typically, the whole process involves procuring a uterus from a live or deceased donor, transplantation, immunosuppression, achieving pregnancy by embryo transfer, and delivery by cesarean section followed by hysterectomy. While live organ donation involves additional risks to the donor due to operative procedures, the clinical outcomes are speculated to be better. Immunosuppression after UT is carried out with a non-teratogenic immunosuppressive regimen and monitored for graft rejection by cervical biopsies [7][156][157]. Embryo transfer is performed using a single euploid blastocyst after 6–12 months [155]. The ensuing pregnancy is then monitored following a protocol for high-risk pregnancy care, and delivered by cesarean section at 37 weeks of gestation, or sooner if indicated. Vaginal delivery is generally not advocated due to concerns about the structural integrity of the graft and sufficiency of vascular anastomoses during contractions. Depending on the reproductive expectations, further embryo transfers can be performed. The uterus is then removed and immunosuppression is stopped to prevent further complications [158]. Although the reproductive scenario in women with MA looks encouraging with UT, it involves ethical issues encompassing both assisted reproduction and organ transplantation [159][160][161]. Adoption is an option for parenthood in couples with MA. It is a legal proceeding that creates a parent–child relationship between persons not related by blood. Adoption laws vary from country to country, and adoption is generally a long process. While it can be legally and socially acceptable, the child is not biologically related to the parents.

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