Clinical Geneticist Self Reflection Essay

      "Play is the work of children.”

This is a small piece of the advice Jeanne Churchill, DNP, CPNP-PC, assistant professor at Columbia Nursing, gives students on the first day of their clinical rotation in pediatrics. Echoing guidance offered by a growing number of clinical instructors in many fields of medicine, she assigns them homework designed to help them reflect on the care they provide to patients and families. The assignment: write an essay about a patient they treat, a clinical situation, or a moment of self-reflection.

Some of our most profound experiences, such as witnessing a birth, suffering with a loved one or comforting someone who is dying can’t be expressed through scientific writing, Churchill says.  Narrative writing allows students to process their experience, explore their understanding of what they are doing, why they are doing it, and the impact it has on themselves and others.

“The Entry to Practice Program is fast paced, and students can become so focused on memorizing facts and knowing the science of nursing that they don’t pause to reflect on the more human aspects of nursing that involve touching patients and listening to them and considering each patient in the context of their individual circumstances,” says Churchill. “By asking them to write a narrative essay about a patient or family member, what I am really asking them to do is to dig deep and reflect on their interactions. These interactions, in addition to the specific indicated medical treatment, can profoundly impact how well the children do.”

The notion of narrative nursing dates back to Florence Nightingale, whose detailed writings about poor conditions in military hospitals during the Crimean War prompted an overhaul of the British army’s health care system. To Churchill, Nightingale’s legacy in narrative nursing can be distilled to a single sentence Nightingale once wrote: “Observation tells us the fact, reflection the meaning of the fact.”

And reflection permeates the essays Churchill’s students produce.

One student, who has had little contact with children before the first day of her pediatrics rotation, reflects on what play means in the course of treating a six-year-old boy with end stage renal disease. Daniel, the name she gives the boy in her essay, has been hospitalized more than 20 times, often for urinary tract infections.  He needs a kidney transplant. And he thinks about his situation in terms of his urine: Pale yellow is good and deep amber is bad; a faint odor is good and a concentrated ammonia-like stench is bad.

Offering his nurse a toy dinosaur, he invites her to play, she recalls:

I am sucked into his world. Daniel grabs the disposable bedside stethoscope and we transition to playing “doctor and patient.” He listens to my heart, and asks me questions: “How old are you? How are things at home? Who is the boss in your house?” Then he looks imploringly: “Do you take all of your medications?” I say yes, and he prods: “Are you lying to me?” And I can’t help but think that this has come from somewhere.

To build trust, even with the youngest patients, you have to show them trust. As his nurse learns from playing that day, trust comes faster when you listen to what they’re really saying and try to speak their language. At the end of her time with Daniel that day, she reflects:

 I think play is the work of children because it’s through play that they make meaning of their lives. It is hard work for them to create and represent that meaning, just as it is hard work for us to accept that six-year-olds need kidney transplants. Illness is a lot to make sense of, but I think I caught a glimpse of Daniel’s attempts when he said, in his best dinosaur-deep voice: “Your pee smells good.

For another student, and another patient, the notion of play looks markedly different. She is treating a five-year-old Saudi Arabian girl with microvillus inclusion disease, a rare genetic disorder that blocks digestion and leads to a life of constant vomiting and explosive diarrhea. The girl speaks limited English, and has been hospitalized for weeks without any family at her bedside because her parents can’t leave her siblings to join her. The hospital assigned a nanny to watch over the girl. And the girl calls this nanny “mama.”

With this young patient, communication with her nurse begins with a ball. This nurse found a ball on the floor and started playing catch with another caregiver in the room.

The girl’s eyes vacillated, hypnotized by the movement off the ball. And then she wanted in. So we threw the ball in a triangle. Instant. Friendship. The ball flew back. And forth. Back. And forth. And she cried with glee. She wasn’t able to go outside and play, but she would enjoy herself. Because this is her reality. She should be learning English in school, but instead, she is learning it in this hospital room. She will learn the word “digestion” before she learns the word “playground.” Because this is her reality.

This girl should be NPO, her nurse knows, which stands for “nil per os” in Latin, or “nothing by mouth.” But this little girl loves drinking from a cup. An exception is made: 

She loves the soothing cool of water sliding down her throat. And even though she is well aware that she will vomit right after, she still drinks. Because despite the consequences, we all know what it is like to do things for instantaneous pleasure. And this is her reality.

In cases like this, Churchill says it’s the job of nurses to go beyond basic patient care to provide the love and support that would ideally be given by a parent. This little girl, who remains in the hospital awaiting evaluation for a small bowel transplant, has no idea what life looks like outside the hospital walls. She has never seen it. 

“As nurses, we are part of her reality, and we try hard to make it a good one,” Churchill says. When students go into the room knowing they will need to create a narrative later, they focus on nuances that might be easy to overlook in a quick check of the chart and a standard patient assessment. With the intensity of focus comes a deeper understanding of patients as individuals, not just clinical problems in need of solutions.

“In pediatrics, the tiny details are very important because young children can’t tell you what’s wrong or how to make it better,” Churchill says. “And sometimes, you can’t make it better, you can just be present and listen to the child’s story until you see even a small way to offer the love and support they would get if they were healthy and at home.”

The two leading European professional societies in the field of assisted reproduction and medical genetics, the European Society of Human Genetics (ESHG) [1] and the European Society for Human Reproduction and Embryology (ESHRE) [2], have been working together since 2004 to evaluate the impact of the rapid progress of research and diagnostic technologies at the interface of assisted reproduction and medical/molecular genetics. Previously, the outcomes of the two consensus meetings have been published [3, 4] in both society journals. The interdisciplinary expert group (further referred to in this paper as ‘the panel’) co-opted several new members and met for the third time in Amsterdam (21–22 September 2016).

Recently, there have been many research developments in the field of genomics, comprising mainly the ongoing transition from traditional 'monogenic genetics' towards comprehensive testing of the human genome by integrating massively parallel sequencing (MPS; or synonym 'next generation sequencing') approaches, together with advanced bioinformatics. Currently, it is possible to elucidate the entire single nucleotide-(SNV), copy number-(CNV) and structural variation (SV) of the human genome, i.e., beyond the original medical indication for which a patient (together with his or her family) was referred for genetic testing. These technological advances are being reflected in expanded carrier screening (ECS), voiding of gamete donor anonymity, preimplantation genetic testing (PGT) and non-invasive prenatal testing (NIPT), and in our understanding of the underlying causes of male and female infertility. Likewise, issues related to mitochondrial replacement in human oocytes and to cross-generational epigenetic inheritance or germline genome editing (GGE) technologies are gradually creating paradigm shifts in the field of assisted reproductive technology (ART). Therefore, the panel mainly focused on the aforementioned selected topics, which are currently being or are likely to be introduced into clinical practice.

Recently, transnational registry data provided evidence that the number of ART cycles in Europe is gradually increasing [5], with more than 640,000 cycles reported in 2012, making a growing contribution to the overall birth rate in many nations in Europe and beyond. The unprecedented complexity of generated research data and the fast (and often hurried) implementation of new technologies into the fields of assisted reproduction as well as of reproductive genetics render the translation of research results into clinical practice challenging. Therefore, due to the increasing population impact of ART and fast developments in research, the introduction both of novel diagnostics [6] and therapies into routine ART clinical practice requires prudence and evidence [7].

It also needs to be acknowledged that there is a blurred boundary between research and its clinical application. Medical and legal liability issues may also arise if the roles and responsibilities of different actors at different stages of translation of research results are not clearly established. Genetic counselling has become increasingly important for patients with various disorders associated with infertility and for future parents to make informed reproductive choices.

The aim of the current consensus paper is to outline the latest developments in ART and genetics/genomics, including their practical implications for clinical management of patients with genetic risks and/or infertility.

ECS in preconception- and gamete donor contexts

An increasing number of preconception carrier tests for autosomal recessive (AR) diseases have become available for couples who want to achieve a pregnancy. Initially, carrier testing was developed for AR diseases that were frequent in specific ethnic groups (for example, Tay–Sachs disease in Ashkenazi Jews, hemoglobinopathies in Mediterranean and African populations and cystic fibrosis in European-derived populations). Various professional societies have recommended preconception carrier testing in high-risk populations (American College of Obsetrics and Gynecology Committee, 2015 [8]) and the American College of Medical Genetics and Genomics 2015 [9, 10]. Given the technological advances in the field of genetic testing, panels for ECS have become broadly available, offering parallel analysis of disease-associated variants in multiple genes, for individuals or couples regardless of their ancestry. A number of such tests are now provided as commercial products, and even within a direct-to-consumer (DTC) setting [11, 12].

The primary objective of ECS in individuals or couples should be to inform them of possible genetic disease risks for their future offspring and their reproductive options in order to foster autonomous reproductive choices [10]. Although the secondary outcome of broadly offered ECS schemes may decrease the frequency of a target condition, as reported, for example, in cystic fibrosis [13], its primary goal is to ensure reproductive autonomy in tested couples. Therefore, non-directive counselling in a pre- and post-test setting is of utmost importance within this context [14]. Still, complex questions may arise if a 'positive' infertile carrier couple would request ART treatment, while rejecting PGD. Would it, then, be morally acceptable or even morally obliged for medical professionals to get involved, given their responsibility to take account of the welfare of the possible future child, to withhold access to assisted reproduction? [15].

Readily available ECS requires a proper implementation strategy [10]. In this regard relevant questions need to be answered first, i.e., what are the responsibilities of health-care professionals who see couples before pregnancy; which genes and diseases should be tested for; which population groups should be targeted; who will pay for ECS; are couples aware that de novo disease-associated variants are not accounted for and that some disease-associated variants (for example, CNV, SNV) in multiple AR conditions are not examined due to the methodology used and its inherent technical limitations?

To ensure successful implementation of population-based ECS, efforts should be made to increase knowledge about genetic disease (i.e., not only on AR disorders) within primary care, among gynaecologists, obstetricians and the general public, in order to create appropriate awareness and address personal benefits of screening in a non-directive manner [16]. Such information should include residual risks of tested diseases and age specific risks of de novo disease-associated variants [17]. Importantly, dominant de novo mutations represent a non-negligible (1–2%) cause of genetic disorders [11, 18].

The ESHG has recommended that in ECS panels 'priority should be given to carrier screening panels that include (a comprehensive set of) severe childhood-onset disorders [10]. Tests should be designed to achieve high clinical validity (clinical sensitivity, negative and positive predictive values (PPV) and should have established clinical utility'. Current and/or future genome-wide approaches to ECS should also strive to minimise incidental findings [19] since the capacity of genetic services to provide follow-up counselling is limited (see, for example, the 2013 overview of clinical genetics staffing in selected European countries from a survey conducted by ESHG in 2013: [20]). Providers should also take into account individual differences in genetic risk and disease severity perception by the general population. Finally, increasing immigration of non-European populations requires expansion of the disease coverage to those particularly occurring in large immigrant ethnic groups and may pose interpretational and counselling challenges both due to a different spectrum of disease-associated variants (often with unclear phenotypic impact, since there is a general lack of evidence in non-European populations because of the scarceness of respective studies) and to divergent cultural perceptions of examined individuals and/or of their families [16, 21, 22].

ECS may be of utility for infertile couples when donor gametes are used to allow the matching of the donor with the respective partner [11, 23]. Couples who already have a child with a monogenic condition may also be interested in avoiding other genetic disorders, and consanguineous couples may also benefit from this approach. Consequently, increased use of ECS may lead to an increased use of PGD and thus less frequent requirement of prenatal diagnosis (PND), both leading to a decrease of elective termination of pregnancy (ETP) for severe genetic disease. Furthermore, antenatal ECS and genetic testing in different phases of life may become intertwined. While early offers of preconception ECS may target serious childhood conditions for which PGD or PND are an option to avoid the live birth of an affected child, ECS may also include treatable conditions (for example, phenylketonuria or medium-chain acyl-CoA dehydrogenase deficiency) to allow for treatment immediately after birth or even during pregnancy (for example, 21-hydroxylase deficiency/congenital adrenal hyperplasia) [24, 25].

Finally, there is increasing evidence that combined low-grade somatic and germline mosaicism eludes current detection techniques and that routine utilisation of blood leucocytes as a proxy for examination of germline variation is insufficient. Therefore, if economically and technically feasible it could be prudent to test in unclear cases genetic variation in the three major embryonic lineages in a given patient in order to estimate the degree of potential post-zygotic mosaicism (i.e., from white blood cells reflecting mesoderm, urine sediment cells—endoderm and dry buccal swab cells or hair follicules—ectoderm). Nonetheless, even after such a complex genetic testing approach mosaicism cannot be completely excluded. In this regard low-grade undetected parental mosaicism may be responsible for erroneously assigned 'de novo status' for observed variation and could skew recurrence risk counselling [26]. Possible germline mosaicism should thus always be mentioned and couples should be informed about the empiric <1% recurrence risk in simplex de novo variants [27].

Thus, ECS may provide a false sense of reassurance, and the lay and professional public should be duly educated in this regard [10].

The panel recommends that national professional organisations in the field of ART and medical/clinical genetics either adopt relevant international guidelines for ECS with modification if required, or develop their own guidelines on how to make ECS responsibly available for their respective populations. The panel also calls upon ECS providers to transparently declare the inherent limitations of the applied methodology.

Advances in genetic testing and voiding of anonymity of gamete donors

Historically, gamete donation has been predominantly anonymous. Moreover, many heterosexual parents choose not to disclose the donor origin to their children, regardless of whether the donation was anonymous or not [28, 29]. Most but not all European countries delegate the decision on whether to disclose to the parents [30].

Some registries, such as the Donor Sibling Registry [31], Donor-Conceived Register [32] and Family Tree DNA [33], allow donors, donor-conceived children and donor siblings to trace each other through genetic ancestry testing, thus possibly reversing the anonymity of the donor. When both parties have consented to find genetic relatives, there is little ethical and legal concern. However, within the context of DTC genetic testing, the discovery of relatives can be accidental and/or relatives may be traced without their prior knowledge or consent. In this regard, DTC genetic testing has already been used by several million people to determine their ancestry [30]. The results of these tests, which are usually provided commercially, enable the consumer to match relatives 'on-line'. This strategy has also already been broadly used by adoptees and foundlings [34]. Moreover, the current affordable costs of DTC genetic testing make it accessible to the majority of consumers in Europe and beyond.

With the growing use of DTC genetic testing, the anonymity of gamete donors can no longer be guaranteed [30, 35]. It does not suffice for the donors to refrain from entering genetic data into the databank. If any of their relatives do, the donor’s family can be 'collaterally' identified. Also children whose parents did not disclose that they were donor-conceived may inadvertently find out about their donor origin. DTC genetic testing may provide interesting information regarding an individual's ancestry (although even in this instance there is a potential for serious misuse of such information [36]) and sometimes even useful information on genetic predispositions. Furthermore, donor-conceived children may also find their half-siblings, the donor himself/herself or other relatives through ancestry testing [37, 38].

Consequently, anonymous gamete donors should be informed that even though the fertility centre or donor agency will strive to protect their identity, their anonymity cannot be absolutely guaranteed. They should be made aware of the fact that even if they do not submit their DNA to one of the donor registries, they themselves or one of their relatives could be identified. Also, the donor's own (future) biological offspring may find half-siblings through these registries. Those donating or conceiving with donated gametes should keep this possibility in mind when deciding whether or not to disclose their donor status/donor conception to their relatives. Another emerging issue is related to the fact that identity disclosure reopens substantiated analyses and legal discussions on numerical limits in donor conception regimes in terms of their potential population genetic impact [39].

The panel recommends that patients undergoing ART treatment with gamete donation should be informed that their children may eventually discover their donor by genetic testing. Furthermore, laboratories offering DTC genetic testing should transparently inform their customers about the potential impact of their services on the possible discovery of non-paternity or unknown family relationships. ART centres that are using anonymous gamete donors need to provide clear information that donors may eventually be traced.

Advances in the genetics of fertility disorders

The fields of male (MI) and female (FI) infertility have witnessed substantial research advances on the underlying genetic causes of infertility. However, it needs to be noted that MI/FI are of complex multifactorial origin and have a very broad spectrum of clinical manifestations. Moreover, the diagnosis of 'infertility' is generally defined in clinical terms only, with little a priori patient stratification involved in scientific studies. Much of the stated research progress is mainly due to the utilisation of MPS and other 'omics' technologies, including state-of-the-art bioinformatics approaches. Nonetheless, despite such advances, current treatment options in MI/FI have not made a substantial progress [40, 41].

Male infertility

The algorithm of genetic testing in MI has not changed. Karyotyping (mainly aimed at examination of gonosomal aberrations, which are the major cause of MI) is followed by testing of disease-associated variants in the CFTR gene and/or Y chromosome microdeletions. However, in ~40% of all cases of MI the underlying genetic pathogenesis is unknown, 'idiopathic MI' [42]. Genetics might play a role but there still needs to be progress in the understanding of the roles of environmental factors, for example, obesity or endocrine disruptors [43], smoking and air pollution [40] and epigenetic mechanisms (see further). Another factor which is important to take into account in Western populations is the increasing paternal age and the concurrent increase of de novo germline disease-associated variants [44].

Recently, a 9-year prospective study from a single centre, comprising 1737 cases, has identified major causes of MI in 40% of all patients with regards to 'reduced total spermatozoa counts' [45]. Additional progress was brought by proteomics and expression profiling analyses [46], including the study of relevant animal models (for example, Mouse Genome Informatics) [47] and of the reproductive tract microbiome [48]. However, application of research outcomes into routine clinical practice has been hampered by unclear definitions of MI cohorts under study, including unclear specification of 'idiopathic MI' (i.e., what exclusion criteria were applied, what exclusion tests were utilised?), which precludes replication or evidence-based meta-analyses [49]. Another confounding factor is related to the fact that many studies use different standards for sperm analyses and do not always adhere to the standardised World Health Organisation criteria [49].

The association of SNV variation [50], drawn from genome-wide association studies (GWAS) in MI, is often based on small cohorts [42]. Nonetheless, there has been marked progress in the identification of disease genes and disease-associated variants in 'non-syndromic' MI. Some of the more prominent instances include teratozoospermia in its rare forms characterised by globozoospermia with disease-associated variation detected in DPY19L2 [51]; SPATA16 [52], macrozoospermia in AURKC [53], alterations of sperm flagella in TUN-STBG1 (Viville et al. 2017; personal communication) and asthenozoospermia in DNAH1 [54], CATSPER1, GALNTL5 [55]. In the case of spermatogenic failure characterised by azoospermia and/or oligozoospermia there has also been progress in terms of identification of disease genes comprising, for example, NR0B1, NR5A1, TEX11, TEX15 [56] and MAGEB4, NANOS1, NR5A1, SOHLH1, SYCE1, TAF4B, WT1 and ZMYND15 (in alphabetical order) (see Table 1 for gene names). Interestingly, TEX11 is an X-linked gene with both SNV and CNV hemizygous disease-associated variants, causing female-transmitted male meiotic arrest [57]. Although there is no predominant disease-associated variation observed thus far, from the clinical point of view identification of such variation associated with spermatogenic failure could indicate the utility of sperm cryopreservation at an appropriate age, to preserve fertility in individuals involved. Novel targeted biomarker assays are under development [40], which could improve genetic counselling and patient stratification for targeted ART treatment.

Awareness of rare genetic syndromes is also relevant in unexplained MI. Although such syndromes are often detected by a medical and family history, typical dysmorphic features, associated disabilities and medical examination, i.e., prior to the diagnosis of MI itself, there could be mild forms of these diseases presenting in adulthood as MI, due to improved standard medical and social care. These clinical entities, for example, comprise hypo-gonadotrophic hypogonadism (Kallmann syndrome—MIM: 308700), where MPS led to the identification of additional candidate genes [58]. Research progress has been made in the case of Klinefelter syndrome by application of testis transcriptomic analysis [59] MI is also commonly associated with rare syndromes with maldescended testes where most of the progress in research is again due to the application of MPS and bioinformatics: Noonan—MIM:163950 [60], Cleidocranial dysplasia—MIM:119600 [61], Bloom—MIM:210900 [62] and Silver–Russel syndromes—MIM:180860 [63]. Likewise, primary ciliary dyskinesia (MIM: 244400) and myotonic dystrophy 1 (MIM: 160900), which are associated in their milder forms with MI, have been subjected to similar research strategies [64, 65].

The panel recommends that standardised clinical terminology and inclusion/exclusion criteria for MI should be used to allow replication studies and evidenced-based meta-analyses to move the field forward. Due to rapid progress in research, selected gene panels may soon become a useful tool allowing identification of additional causes of MI, and thus improve genetic- and reproductive counselling, facilitate patient stratification and therefore enable more precise ART approaches.

Female infertility

In the same way as in MI, research on the underlying genetic causes of FI is quickly advancing. Nonetheless, relatively little is still known about the genetic background of most cases of FI or female subfertility (FSF), and even less is translated into novel clinical practice. Evidently, FI is of complex multifactorial origin as reflected by the clinical and genetic heterogeneity of the cohorts under study, which then hinders replicability of previously performed analyses. Presumably hundreds of genes have to interact in a precise manner during sex determination, gametogenesis, complex hormone actions/interactions and embryo implantation and its early development, in order to create a healthy offspring. Thus, disorders related to FI/FSF are expected to be highly polygenic [66]. Considering that in mice more than 500 genes have already been associated with FI (MGI, see above) many more disease genes are waiting to be identified in humans in the coming years. Non-coding RNA's and epigenetic modifications have also been implicated in the control of ovarian function and thus their disturbances are likely to be associated with FI [67].

Chromosomal aberrations remain a major known cause of premature ovarian insufficiency (POI) and recurrent miscarriages, thus decreasing the chance of successful pregnancy [68, 69]. A sizeable proportion of disorders of sexual development are also caused by gonosomal aberrations, and for other aetiologies, such as hypothalamic–pituitary–gonadal deficiencies, many additional disease-causing genes have already been identified [70].

There has been some progress in understanding of the role of genetic disease-causing genes in common multifactorial disorders such as polycystic ovary syndrome (PCOS) and endometriosis, each affecting around 10% of women with FI/FSF. In PCOS, better patient stratification and functional genomics could provide novel research avenues [71, 72], while in endometriosis [73] abnormal epigenetic mechanisms in stromal cells may play a pathogenic role.

Progress has also been achieved in the identification of monogenic causes of FI/FSF, in particular for 'non-syndromic' POI for which multiple X-linked and autosomal genes have been identified as recently reviewed [74]. POI is highly clinically heterogeneous and is associated either with ovarian dysgenesis reflected by primary amenorrhoea or with secondary amenorrhoea. However, the majority of POI cases are 'idiopathic'. Additional disease-causing genes have been identified by candidate gene approaches, GWAS and/or whole-exome analyses utilising MPS. However, disease-associated variants in these genes were reported in a rather small number of cases, some being confined to specific populations [66, 67, 75]. Interestingly, recent studies revealed a complex genetic architecture of POI [76]. The authors screened both known and potential candidate genes in a clinically well characterised cohort of patients. Disease-associated variants were found, for example, in BMP15, FIGLA, FOXL2, GALT, GDF9, LHX8,NOBOX, REC8, SMC1β and SOHLH1 (in alphabetical order), which fall into transcription factor TGF-β ligand, enzyme and 'meiosis' functional categories [53]. In the latter category, other authors have reported disease-associated variants in STAG3 [77], SYCE1 [78], HFM1 [79], MCM8 and MCM9 [80] (Table 1 for gene names). From the clinical point of view, variation linked to POI may also predict the risk of a premature menopause in affected families [67, 81].

The list of disease-causing genes related to 'syndromic' POI, where its pathogenesis is related to other clinical entities, was reviewed elsewhere [75]. In many instances, these multi-system syndromes rather than FI itself lead to the clinical diagnosis and referral for genetic testing, often in the pre-reproductive age. Disease-associated variants in the FOXL2 gene provide an example. Altered function of this gene causes the blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; MIM: 110100) with or without POI. Progressive external ophthalmoplegia (MIM: 157640) together with other symptoms, including POI, is caused by disease-associated variants in POLG thereby implicating mitochondria-related pathology [82]. Disease-associated variants in GALT (MIM: 230400 for galactosaemia), PMM2 (MIM: 212065 for congenital disorders of glycosylation type Ia), CLPP (MIM: 614921 for congenital disorders of glycosylation type It), NOG (MIM: 185800 and 186500 for symphalangism 1a and multiple synostoses syndrome 1, respectively), EIF2B2 (MIM: 603896 for leukoencephaly with vanishing white matter syndrome) and HARS2 (MIM: 157400 for progressive external ophtamoplegia with mitochondrial DNA (mtDNA) deletions) have also been secondarily implicated in POI (see above) (see Table 1 for gene names). Likewise, disease-associated variants in several different disease-causing genes (CLPP, HARS2, HSD17B4, LARS2 and TWNK; in alphabetical order (see Table 1 for gene names) are implicated in the development of the Perrault syndrome (MIM: 233400), which associates sensorineural hearing loss and ovarian dysfunction [83]. Finally, CGG expansions in the 'pre-mutation range' in the FMR1 gene remain a well-established cause of isolated POI, more frequent in families with Fragile X syndrome (MIM: 300624), than in sporadic cases of POI.

Recently, dominant negative disease-associated variants in the TUBB8 gene, causing defects in spindle assembly and leading to oocyte maturation arrest, have been described in several families. This autosomal disorder was either male-transmitted or de novo and its phenotype was female-specific [84]. Disease-associated variants in TLE6 were linked to preimplantation embryonic lethality [85]. Although the existence of the genuine empty follicle syndrome is still a matter of debate, disease-associated variants in the LH/CG receptor gene (LHCGR) have been reported in this disorder [86].

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