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

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.

Natural history of adults with KBG syndrome: a physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptopms included mild/borderline intellectual disability (n=22); gross and/or fine motor difficulties (n=15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n=26); nonverbal (n=3), seizures with various seizure types and treatment responses (n=10); ophthalmological comorbidities (n=20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n=2) and autoimmune conditions (n=4). Education, work, and residence varied and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both datasets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.

Understanding the Diagnostic Odyssey of Women with Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome in Denmark: A Qualitative Interview Study.

STUDY OBJECTIVE: The diagnosis of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is often a lengthy process that typically occurs during late adolescence. To support optimized and patient-centered care, this study aimed to investigate how women with MRKH syndrome experience the diagnostic process. METHODS: From January 2021 to March 2021, we conducted in-depth interviews with 18 Danish women (≥25 years) diagnosed with MRKH syndrome. The interviews lasted a median of 92 minutes (range: 67-117). Data were analyzed using thematic analysis. RESULTS: As teenagers or young women at the time, all women had experienced the diagnostic process in the nonspecialized healthcare sector as deeply upsetting due to distressing gynecological examinations, use of inappropriate language, and considerable diagnostic delay. When reaching the specialized health care sector, questions could finally be answered, but this information and support did not significantly alter their feelings of being "deviant" or "flawed". The women continued their diagnostic odyssey beyond the health care system and found online communities that gave them valuable support in living with MRKH syndrome. CONCLUSION: Women experience the diagnostic odyssey of MRKH syndrome as upsetting and potentially traumatizing beyond the diagnosis. Healthcare professionals can influence young women's understanding and experience of MRKH syndrome by using inclusive language (eg, avoiding "deformity") and addressing all that is normal and functioning (eg, external genitalia and potential for sexual pleasure). In nonurgent conditions, young women should be given the choice to delay a genital examination.

A life course perspective on Mayer-Rokitansky-Küster-Hauser syndrome: women's experiences and negotiations of living with an underdeveloped uterus and vagina.

PURPOSE: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by the absence or underdevelopment of the uterus and upper part of the vagina. It is usually diagnosed during adolescence, and the present study investigates how women experience and negotiate to live with MRKH syndrome long-term. METHODS: From January to March 2021, eighteen Danish women with MRKH syndrome participated in semi-structured interviews via video conference. The mean time since diagnosis was 11.5 years. A thematic analysis using the life course framework as a theoretical approach was applied. RESULTS: The analysis identified the diagnosis as a turning point, that dramatically altered the women's imagined futures. Not conforming to dominant social norms regarding sexuality and pregnancy meant that the women continuously managed and negotiated the meaning and impact of MRKH syndrome in relation to the five principles of the life course perspective: (1) Lifelong development, (2) Timing, (3) Human agency, (4) Linked lives, and (5) Historical time and place. CONCLUSION: Using the life course framework contributed to a holistic understanding of life with MRKH syndrome by showing how the meaning and consequences of the congenital condition changed over time and in adaptation to gendered and age-related social norms and expectations.IMPLICATIONS FOR REHABILITATIONThe perceived meaning and impact of living with Mayer-Rokitansky-Küster-Hauser syndrome change over time, and women's information and support needs thus change accordinglySensitive, clinical communication is essential when discussing treatment optionsOnline communities may provide support and reduce feelings of loneliness.

The clinical use of polygenic risk scores.

Polygenic risk scores (PRS) identify at-risk individuals for many common diseases. A discussion of strengths and limitations is carried out in this review. PRS complement traditional genetic testing and have shown utility in establishing a proper diagnosis and guiding primary and secondary prevention. Some individuals with high PRS have risks similar to those with monogenic predisposition. Limitations include potential misinterpretations, problems with application across ancestries, and limited usefulness in low-heritability traits. Despite its shortcomings PRS are predicted to play major roles in the future of personal medicine and genetic testing.

Congenital mirror movements are associated with defective polymerisation of RAD51.

BACKGROUND: Mirror movements are involuntary movements of one hand that mirror intentional movements of the other hand. Congenital mirror movements (CMM) is a rare genetic disorder with autosomal dominant inheritance, in which mirror movements are the main neurological manifestation. CMM is associated with an abnormal decussation of the corticospinal tract, a major motor tract for voluntary movements. RAD51 is known to play a key role in homologous recombination with a critical function in DNA repair. While RAD51 haploinsufficiency was first proposed to explain CMM, other mechanisms could be involved. METHODS: We performed Sanger sequencing of RAD51 in five newly identified CMM families to identify new pathogenic variants. We further investigated the expression of wild-type and mutant RAD51 in the patients' lymphoblasts at mRNA and protein levels. We then characterised the functions of RAD51 altered by non-truncating variants using biochemical approaches. RESULTS: The level of wild-type RAD51 protein was lower in the cells of all patients with CMM compared with their non-carrier relatives. The reduction was less pronounced in asymptomatic carriers. In vitro, mutant RAD51 proteins showed loss-of-function for polymerisation, DNA binding and strand exchange activity. CONCLUSION: Our study demonstrates that RAD51 haploinsufficiency, including loss-of-function of non-truncating variants, results in CMM. The incomplete penetrance likely results from post-transcriptional compensation. Changes in RAD51 levels and/or polymerisation properties could influence guidance of the corticospinal axons during development. Our findings open up new perspectives to understand the role of RAD51 in neurodevelopment.

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

Autosomal dominant sleep-related hypermotor epilepsy caused by a previously unreported CHRNA4 variant.

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is a rare heritable form of epilepsy. It is characterized by hypermotor seizures occurring mainly during sleep. Seizures are typically abrupt in onset and offset and tend to increase in complexity and duration during the night. ADSHE is inherited in an autosomal dominant manner, and penetrance is estimated to be 70%. We describe two brothers with ADSHE with a previously unreported variant in CHRNA4, and the effect of medical treatment with carbamazepine. We highlight the relevance of genetic testing in patients with atypical and clustering episodes of nightmares, night terrors, or panic attacks, as these patients could be misdiagnosed, and instead be suffering from ADSHE, a potentially treatable condition.

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression.

Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning-based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.

What Is Abnormal in Normal Karyotype Acute Myeloid Leukemia in Children? Analysis of the Mutational Landscape and Prognosis of the TARGET-AML Cohort.

Normal karyotype acute myeloid leukemia (NK-AML) constitutes 20-25% of pediatric AML and detailed molecular analysis is essential to unravel the genetic background of this group. Using publicly available sequencing data from the TARGET-AML initiative, we investigated the mutational landscape of NK-AML in comparison with abnormal karyotype AML (AK-AML). In 164 (97.6%) of 168 independent NK-AML samples, at least one somatic protein-coding mutation was identified using whole-genome or targeted capture sequencing. We identified a unique mutational landscape of NK-AML characterized by a higher prevalence of mutated CEBPA, FLT3, GATA2, NPM1, PTPN11, TET2, and WT1 and a lower prevalence of mutated KIT, KRAS, and NRAS compared with AK-AML. Mutated CEBPA often co-occurred with mutated GATA2, whereas mutated FLT3 co-occurred with mutated WT1 and NPM1. In multivariate regression analysis, we identified younger age, WBC count ≥50 × 109/L, FLT3-internal tandem duplications, and mutated WT1 as independent predictors of adverse prognosis and mutated NPM1 and GATA2 as independent predictors of favorable prognosis in NK-AML. In conclusion, NK-AML in children is characterized by a unique mutational landscape which impacts the disease outcome.

Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets.

Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.

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

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.