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Han G Brunner

Publications and source records attributed to Han G Brunner.

At least 19 recordsLinked to original sources
PubMed2026

Mapping ovarian cellular and molecular landscape across the lifespan of women: a scoping review.

BACKGROUND: With growing interest in ART, fertility preservation, and postmenopausal health of women, reproductive medicine is increasingly focused on characterizing oocytes and ovarian tissue composition, as well as understanding the molecular mechanisms that guide ovarian function throughout its lifecycle. High-throughput omics technologies have enabled the characterization of different molecular layers, leading to substantial advances in our understanding of their complex dynamics. However, not all molecular aspects are studied equally, and studies examining the same modalities often show inconsistencies, underscoring the need for data standardization and highlighting the potential for using transformative artificial intelligence and machine-learning (AI/ML) methods for ovary studies. OBJECTIVE AND RATIONALE: This study aims to evaluate how multi-omic studies have advanced our understanding of the ovarian lifecycle from fetal development to postmenopause. We systematically reviewed published studies that have investigated molecular/omic layers, including the genome, methylome, transcriptome, and proteome throughout ovarian development and aging. Our analysis identified key molecular and cellular patterns, highlighted inconsistencies across studies and addressed gaps in data analysis, interpretation, and reproducibility to guide future research. SEARCH METHODS: We conducted a systematic literature search of Medline (PubMed), Embase (Ovid), and Web of Science Core Collection (Clarivate) using a combination of controlled and free text terms for human ovary, oogenesis, folliculogenesis, ovary development and (epi)genome, transcriptome, proteome, and multi-omic mechanisms to find relevant articles published before August 2025. To focus the scope of the current review, studies of domesticated and farm animals, rodents and other model organisms, non-human primates, as well as those examining various human ovarian pathologies were excluded. OUTCOMES: The search identified 23 546 studies for screening, of which 637 full-text studies were assessed for eligibility. Subsequently, we extracted data from 121 studies. Most studies analyzed the transcriptome of oocytes, granulosa cells, and ovarian tissue from reproductive-age individuals (n = 91), with fewer studies examining samples from individuals of advanced reproductive age (n = 45) and fetal (n = 16) samples. Transcriptome analyses were most common (n = 103, 85%), followed by proteome (n = 19, 16%) and epigenome (n = 14, 12%) studies. We found substantial variation in how studies defined and reported participants' groups as well as in their sequencing technologies and data analysis methods, with a lack of standardized reporting of background clinical information, data analysis methods, and pipeline details. The key findings underscore the prevailing consensus on genes defining major ovarian cell types and their roles throughout the ovarian lifespan, from prenatal development to postmenopausal transformation. This review highlighted the underrepresentation of certain patient groups, particularly prepubertal and peri-/postmenopausal individuals, among researched populations, due to obvious clinical and ethical reasons. WIDER IMPLICATIONS: This scoping review offers a comprehensive overview and benchmark of the current state of high-throughput omics-based research on ovarian cellular composition and molecular dynamics. To address these shortcomings, we propose general recommendations for multi-omics ovary studies and emphasize the necessity for more thorough multi-omic data integration by effectively applying novel AI/ML approaches. They can potentially improve the quality of multi-omics analyses at both single-cell and tissue levels despite limited sample sizes and enable integration of molecular profiling data with clinical and radiology datasets, enabling a more comprehensive understanding of ovarian biology. Such advancements can enhance reproducibility of research findings and guide future research to deepen our understanding of ovarian biology and ultimately support the development of medical technologies for better preserving fertility and alleviating infertility. REGISTRATION NUMBER: A protocol was published a priori on the Open Science Framework (https://osf.io/z38gb/).

Female↗
PubMed2006

Unfavorable pathological characteristics in familial colorectal cancer with low-level microsatellite instability.

A high degree of microsatellite instability (MSI) in colorectal cancer (CRC) is a hallmark of hereditary non-polyposis colorectal cancer (HNPCC), caused by germline defects in the mismatch repair (MMR) genes. A low degree of instability (less than 30% of the microsatellites) is seen in a subset of tumors. To clarify the significance of this low degree of MSI phenotype, we studied the differences between patients with colorectal tumors with high-level, low-level and no MSI. Colorectal tumors with no (n = 68) and low-level (n = 18) MSI of patients clinically suspected of HNPCC were compared to colorectal tumors with high-level MSI (n = 12) of patients that carry a pathogenic germline mutation in a MMR gene. Compared to tumors with no MSI, tumors with low-level MSI were classified more frequently as stage T3 or T4 (100% vs 68% respectively), and showed less immune response (P = 0.02). No significant differences in familial CRC risk were found by comparing pedigrees of these two groups of tumors. Compared to the group of tumors with high-level MSI, the group of tumors with low-level MSI had a less suspicious family history, a higher percentage of lymph node metastasis (56 vs 17%), and less immune response. Thus, with respect to genetic risks, familial CRC can be divided into two groups: Tumors with high-level MSI and tumors with low-level or no MSI. However, tumors with low-level MSI show unfavorable pathological characteristics compared to tumors with no and tumors with high-level MSI. These differences suggest a distinct underlying biology of CRC with low-level MSI.

Adenocarcinoma↗
PubMed2006

Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes.

Hereditary congenital facial palsy (HCFP) is an autosomal-dominant disorder consisting of paresis or paralysis of the VIIth (facial) cranial nerve. Genetic heterogeneity for this disorder has been suggested based on linkage analysis in two large Dutch families. Two loci have been identified, one on chromosome 3q21.2-q22.1 (HCFP1) and another on chromosome 10q21.3-q22.1 (HCFP2). Here, we report linkage analysis in a large Pakistani family with dominant congenital facial palsy. A region cosegregating with the disorder was identified on the long arm of chromosome 3, which overlaps with the previously identified HCFP1 locus on chromosome 3q21-q22, thus confirming the involvement of this locus in HCFP. The critical region could be reduced from 5.7 to 3.0 cM between the markers D3S3607 and GDB ID:11524500. In addition, mutation analysis on seven candidate genes: KLF15, FLJ40083, PODXL2, TMCC1, PLEXIN-A1, PLEXIN-D1, and GATA-2, was performed. All genes are located within the critical interval of the Dutch HCFP1 family. The genes PODXL2, PLEXIN-D1, GATA-2, and TMCC1 are also located within the smaller critical interval of the Pakistani HCFP family. Based on the results obtained, all seven genes could be excluded as causative genes in HCFP.

Chromosome Mapping↗
PubMed2006

A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism.

Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism.

Adolescent↗
PubMed2006

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

The prevalence of congenital heart defects is approximately 1% of all live births. Identifying the genes responsible for cardiac malformation is the first step to understand pathogenesis. Heterozygous mutations in the CSX/NKX2-5 (NKX2E) gene have been identified to cause atrial septal defect (ASD) and/or atrioventricular (AV) conduction disturbance in some families. However, there is great variability in expressivity of the phenotype between the patients with a CSX/NKX2-5 mutation. We screened four sporadic patients and three index cases of families with ASD and/or conduction defects. In one of them, a CSX/NKX2-5 mutation was identified. This novel mutation (p.Tyr256X) was inherited in a three-generation family causing five individuals to have cardiac anomalies ranging from ASD to arrhythmias. Interestingly, all the observed AV conduction disturbances were at the nodal level, manifesting first as an AV block of the first degree and evolving toward a second-degree block. Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients.

Female↗
PubMed2006

Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1.

Holoprosencephaly (HPE) is the most common developmental defect affecting the forebrain and midface in humans. The aetiology of HPE is highly heterogeneous and includes both environmental and genetic factors. Here we report on a boy with mild mental retardation, lobar HPE, epilepsy, mild pyramidal syndrome of the legs, ventricular septal defect, vesicoureteral reflux, preaxial polydactyly, and facial dysmorphisms. Genome-wide tiling path resolution array based comparative genomic hybridisation (array CGH) revealed a de novo copy-number gain at 5q35.1 of 1.24 Mb. Additional multiplex ligation-dependent probe amplification screening of a cohort of 31 patients with HPE for copy-number changes at the 5q35.1 locus did not reveal any additional genomic anomalies. This report defines a novel 1.24 Mb critical interval for HPE and preaxial polydactyly at 5q35.1. The duplicated region encompasses seven genes: RANBP17, TLX3, NPM1, FGF18, FBXW11, STK10, and DC-UbP. Since FBXW11 is relatively highly expressed in fetal brain and is directly involved in proteolytic processing of GLI3, we propose FBXW11 as the most likely candidate gene for the HPE and prexial polydactyly phenotype. Additional research is needed to further establish the role of genes from the 5q35.1 region in brain and limb development and to determine the prevalence of copy number gain in the 5q35.1 region among HPE patients.

Adolescent↗
PubMed2006

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

Animals↗
PubMed2006

Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.

Alleles↗
PubMed2006

Pattern of p63 mutations and their phenotypes--update.

Heterozygous mutations in the transcription factor gene p63 cause at least six different syndromes with various combinations of ectodermal dysplasia, orofacial clefting and limb malformations. Here we will present an update of mutations in the p63 gene together with a comprehensive overview of the associated clinical features in 227 patients. These data confirm the previously recognized genotype-phenotype associations. Moreover, we report that there is a large degree of clinical variability in each of the p63-associated disorders. This is illustrated by the different phenotypes that are seen for the five-hotspot mutations that explain almost 90% of all EEC syndrome patients.

Abnormalities, Multiple↗
PubMed2006

Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome.

Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.

Abnormalities, Multiple↗
PubMed2006

Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.

A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.

Abnormalities, Multiple↗
PubMed2006

Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes.

Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases.

Computational Biology↗
PubMed2006

Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.

Abnormalities, Multiple↗
PubMed2006

The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (39 newly investigated and 20 published elsewhere). We identified the first complete deletions of EFNB1, catalogued 27 novel intragenic mutations, and used Pyrosequencing and analysis of nearby polymorphic alleles to quantify mosaic cases and to determine the parental origin of verified germline mutations. Somatic mosaicism was demonstrated in 6 of 53 informative families, and, of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father. We conclude that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline (which present as affected female offspring) combined with reduced reproductive fitness in affected females. Postzygotic mutations also contribute to the female preponderance, whereas true nonpenetrance in males who are hemizygous for an EFNB1 mutation appears unusual. These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations.

Craniofacial Abnormalities↗
PubMed2006

Mutations in different components of FGF signaling in LADD syndrome.

Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by lacrimal duct aplasia, malformed ears and deafness, small teeth and digital anomalies. We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand. These findings increase the spectrum of anomalies associated with abnormal FGF signaling.

Abnormalities, Multiple↗
PubMed2006

The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation.

The importance of O-glycosylation of alpha-dystroglycan (alpha-DG) is evident from the identification of POMT1 mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity. WWS patients are characterized by congenital muscular dystrophy (CMD) with severe brain and eye abnormalities. This suggests a crucial role for alpha-DG during development of these organs and tissues. Here we report new POMT1 mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygous POMT1 mutations in four unrelated families that result in a less severe phenotype than WWS, characterized by CMD with calf hypertrophy, microcephaly, and mental retardation. Compared to WWS patients, these patients have milder structural brain abnormalities, and eye abnormalities were absent, except for myopia in some cases. In these patients we postulate that one or both transcripts for POMT1 confer residual protein O-mannosyltransferase activity. Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations.

Adolescent↗
PubMed2006

Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.

Amino Acid Sequence↗
PubMed2006

A text-mining analysis of the human phenome.

A number of large-scale efforts are underway to define the relationships between genes and proteins in various species. But, few attempts have been made to systematically classify all such relationships at the phenotype level. Also, it is unknown whether such a phenotype map would carry biologically meaningful information. We have used text mining to classify over 5000 human phenotypes contained in the Online Mendelian Inheritance in Man database. We find that similarity between phenotypes reflects biological modules of interacting functionally related genes. These similarities are positively correlated with a number of measures of gene function, including relatedness at the level of protein sequence, protein motifs, functional annotation, and direct protein-protein interaction. Phenotype grouping reflects the modular nature of human disease genetics. Thus, phenotype mapping may be used to predict candidate genes for diseases as well as functional relations between genes and proteins. Such predictions will further improve if a unified system of phenotype descriptors is developed. The phenotype similarity data are accessible through a web interface at http://www.cmbi.ru.nl/MimMiner/.

Chromosome Mapping↗