Eur J Med Genet [JOURNAL]
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200 papers
Epileptic seizures and EEG findings in 3p deletion syndrome involving SLC6A1.
Oguri S, Inoue M, Kobayashi O … +2 more , Tomoki M, Ihara K
Eur J Med Genet · 2025 Aug · PMID 40517887 · Publisher ↗
3p Deletion syndrome is a rare genetic disorder characterized by intellectual disability, growth delay, hypotonia, and distinctive facial features, with considerable phenotypic variability. Previous reports have highligh...
3p Deletion syndrome is a rare genetic disorder characterized by intellectual disability, growth delay, hypotonia, and distinctive facial features, with considerable phenotypic variability. Previous reports have highlighted the significance of deletions within the 3p25.3 region contributing to the development of Angelman-like features, such as stereotypic movements, a happy demeanor, epilepsy, and characteristic electroencephalogram (EEG) patterns. This study analyzed 22 patients of 3p deletion syndrome, focusing on epilepsy and EEG findings. A newly defined short smallest region of overlap (sSRO) within 3p25.3, encompassing approximately 52 kb and partially including SLC6A1 and SLC6A11, was associated with Angelman-like features, particularly epilepsy and EEG patterns. Patients with sSRO deletions exhibited a high incidence of seizures (60 %), characterized by myoclonic or absence seizures, with EEG showing generalized high-amplitude slow waves. In contrast, larger deletions beyond the sSRO were linked to dysmorphological features of 3p-syndrome, generalized tonic-clonic seizure, and non-specific EEG findings. These findings suggest that SLC6A1 dysfunction contributes to epilepsy and EEG abnormalities, possibly via impaired GABA transport, whereas patients with larger or non-overlapping deletions exhibited more typical 3p-syndrome features, suggesting that multiple neurological genes in the broader deletion region may independently contribute to more severe neurological phenotypes. In conclusion, it is important to consider GABA-related disorders, including a specific chromosomal abnormality known as 3p-syndrome with a microdeletion in the SRO region, when observing characteristic epilepsy and EEG findings resembling Angelman syndrome.
A novel RORA genetic variant associated with early-onset obesity and insomnia.
Ouellette A, Allain EP, Almaghraby A … +2 more , Bouhamdani D, Ben Amor M
Eur J Med Genet · 2025 Aug · PMID 40516851 · Publisher ↗
Retinoic acid-related orphan receptor alpha (RORA) pathogenic variants cause intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA). Herein, we present a female patient with a novel he...
Retinoic acid-related orphan receptor alpha (RORA) pathogenic variants cause intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA). Herein, we present a female patient with a novel heterozygous likely pathogenic RORA variant, c.484C > T p.(Arg162∗), with a clinical manifestation overlapping IDDECA. The patient also presented previously undocumented symptoms, namely, early-onset obesity and insomnia. Furthermore, parental testing revealed inheritance from the mother who presented a congruent phenotype. This suggests a role for RORA in both sleep and metabolism whilst extending the phenotypic spectrum of IDDECA. Notwithstanding, more fundamental work is needed to delineate the role of RORA variants in disease.
Clinical variability in individuals with ATR-X syndrome in the Netherlands.
Noordhuis-Zijderveld A, Festen DAM, Kharl A … +5 more , van Gastel M, Hartman M, Bruggenwirth HT, Zeidler S, Valstar MJ
Eur J Med Genet · 2025 Aug · PMID 40484370 · Publisher ↗
BACKGROUND: The Alpha Thalassemia mental Retardation syndrome, X-linked (ATR-X syndrome, MIM: 301040) is a rare genetic disorder characterized by alpha thalassemia, intellectual disability, peculier facial characteristic...
BACKGROUND: The Alpha Thalassemia mental Retardation syndrome, X-linked (ATR-X syndrome, MIM: 301040) is a rare genetic disorder characterized by alpha thalassemia, intellectual disability, peculier facial characteristics and genital abnormalities. Detailed information regarding the clinical phenotype is lacking. AIMS: Detailed descriptions of the clinical phenotype are rare. The aim of this study was to describe the clinical phenotype of ATR-X syndrome. METHODS: Data was collected through questionnaires, interviews, physical examination and the study of medical records. RESULTS: Twenty-two individuals, aged 2-68 years old, were included. Three individuals were deceased at the time of the study. The individuals had a variable degree of intellectual disability. Alpha thalassemia was found in 30 % and genital anomalies in 70 % of the individuals. First clinical signs of the syndrome were most frequently feeding problems, started in the neonatal period in the majority. Other main reported health problems were reflux (59 %), constipation (72 %), periods of anorexia and adipsia (45 %), heart defects (28 %), epilepsy (33 %), scoliosis/kyphosis (48 %), visual impairment (61 %) and hearing loss (38 %). Behavioral problems (86 %) and sleeping problems (64 %) also occurred frequently. CONCLUSION: We report on the largest cohort of clinically studied individuals with ATR-X syndrome, including the eldest individuals, reported to date. Clinical knowledge is essential to improve care and to evaluate future therapies for this group.
Parental communication about inherited conditions with young Children: Insights from genetic professionals in Portugal.
Seidi C, Sousa L, Mendes Á
Eur J Med Genet · 2025 Aug · PMID 40472929 · Publisher ↗
Genetic healthcare professionals (GHP) are key in supporting parents in communicating about inherited genetic conditions (IGC) with their young children. This study explored the attitudes, clinical practice and perceptio...
Genetic healthcare professionals (GHP) are key in supporting parents in communicating about inherited genetic conditions (IGC) with their young children. This study explored the attitudes, clinical practice and perceptions of Portuguese GHP' regarding parental communication about IGC with young children. We conducted an observational and cross-sectional study with 32 GHP, 75 % of whom were women, and 37.5 % were aged 31-40 years old. The survey included sociodemographic and professional questions, along with 35 statements to be answered on a 4-point Likert scale (ranging from 1- strongly disagree to 4- strongly agree). Key findings show that GHP: (i) perceive that parents fear the impact of genetic information on their children's emotional wellbeing (3.53 ± 0.51), are receptive to support from GHP (3.16 ± 0.57), and should tailor communication to children's developmental stage (3.56 ± 0.50); (ii) report being available to support parents when asked (3.56 ± 0.62) and encourage parents to communicate openly (3.47 ± 0.57); and (iii) assess parents' level of understanding about the IGC (3.41 ± 0.56), raise parents' awareness of the importance of informing their children (3.28 ± 0.52), and support parents in adapting communication to the type of IGC (3.28 ± 0.58), and the child's developmental stage (3.22 ± 0.55). Results emphasize critical role of GHP in facilitating parent-child communication about IGC, highlighting their commitment to supporting these sensitive conversations.
Novel STAG2 variant expands Mullegama-Klein-Martinez Syndrome phenotype.
Duff C, Allawendy S, Green AJ … +3 more , Riordan M, Carolan E, McBrien J
Eur J Med Genet · 2025 Aug · PMID 40456439 · Publisher ↗
We present a novel case of a female patient with a de novo heterozygous splice site pathogenic variant STAG2 (NM_001042749.3):c.1196 + 4_1196+7del. The STAG2 gene encodes "Stromal Antigen 2" (STAG2), a fundamental subuni...
We present a novel case of a female patient with a de novo heterozygous splice site pathogenic variant STAG2 (NM_001042749.3):c.1196 + 4_1196+7del. The STAG2 gene encodes "Stromal Antigen 2" (STAG2), a fundamental subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Pathogenic STAG2 gene variants are associated with Mullegama-Klein-Martinez Syndrome (MKMS), a rare X-linked cohesinopathy. This patient exhibits symptoms not previously associated with MKMS, thereby expanding the known clinical phenotype of this rare disease. The patient has severe intellectual disability, microcephaly, short stature, and a single front tooth. She also has an ectopic posterior pituitary gland, resulting in vasopressin deficiency (formerly known as central diabetes insipidus), which was associated with adipsia, causing profound hypernatraemic dehydration and acute renal failure necessitating peritoneal dialysis. STAG2 pathogenic variants should prompt in-depth imaging of the pituitary fossa for pituitary malformations. Clinical and biochemical screening and surveillance should be performed to identify pituitary dysfunction.
Partial 3q tetrasomy: Defining the syndrome, neocentromeres, and an additional case report.
Hauberg ME, Jønch AE, Fagerberg CR
Eur J Med Genet · 2025 Aug · PMID 40451420 · Publisher ↗
Partial 3q tetrasomy is an ultra-rare genetic condition, with a phenotype that has hitherto not been comprehensively reviewed. In this paper we report the 18th case and re-evaluate those previously published. The present...
Partial 3q tetrasomy is an ultra-rare genetic condition, with a phenotype that has hitherto not been comprehensively reviewed. In this paper we report the 18th case and re-evaluate those previously published. The present case presented with dysmorphic features, malformations, cognitive deficits, end-stage renal disease, a surgically corrected tethered chord/scoliosis along with skin pigmentary changes and had remained without a diagnosis for 23 years. Blood and fibroblast karyotyping and exome sequencing yielded a normal result. Chromosomal microarray analysis on uncultured skin biopsies showed a mosaic amplification of the terminal 34 Mb of 3q. Subsequent fluorescence in situ hybridisation on cultured cells showed that a few metaphases contained a small supernumerary marker chromosome (sSMC) consisting of two head-to-head copies of the amplified 3q-material with neocentromere formation, the lower degree of mosaicism in karyotyping being ascribed to loss of sSMC upon culturing. Reviewing the published cases of partial 3q tetrasomy cases we find pigmentary changes along the lines of Blaschko, cognitive deficits, spinal malformations, depressed nasal bridge, and palatal deformities to be frequent findings, and highlight a phenotypic overlap with partial 3q trisomy. Symptoms spanned from mild to severe, likely depending on both the size of the amplification and the degree of mosaicism.
Wolcott-Rallison syndrome - crosstalk between PERK- EIF2A and type II interferon signaling.
Konduri M, Boe D, Yazigi N … +9 more , Khan K, Ward BR, Saldana BD, Cavener D, Kallakury B, Kroemer A, Matsumoto C, Fishbein T, Ekong UD
Eur J Med Genet · 2025 Aug · PMID 40441422 · Publisher ↗
Immune activation is not reported in children with Wolcott-Rallison syndrome (WRS). We observed a pattern of immune activation pre-transplant in three children with WRS that was consistent with increased interferon-γ (IF...
Immune activation is not reported in children with Wolcott-Rallison syndrome (WRS). We observed a pattern of immune activation pre-transplant in three children with WRS that was consistent with increased interferon-γ (IFN-γ) and its regulated chemokine, CXCL9 in plasma, and bone marrow that demonstrated scattered hemophagocytosis. One child developed hemophagocytic lymphohistiocytosis after liver transplantation that was fatal. Children with WRS should undergo evaluation for inflammatory biomarkers before transplant to aid in diagnosis of and prompt treatment of hyperinflammatory syndromes. Early recognition can prevent fatal outcomes.
Variable expressivity of a transmitted pathogenic KAT6B variant.
Rasmussen NB, Gregersen PA, Nielsen TØ … +6 more , Lyngdorf LG, Nielsen CK, Kruse C, Bayat M, Campeau PM, Skakkebæk A
Eur J Med Genet · 2025 Aug · PMID 40441421 · Publisher ↗
Pathogenic variants in KAT6B (Lysine acetyltransferase 6B) are associated with two clinically overlapping autosomal dominant disorders Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736), and Genitopatella...
Pathogenic variants in KAT6B (Lysine acetyltransferase 6B) are associated with two clinically overlapping autosomal dominant disorders Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736), and Genitopatellar syndrome (GPS) (OMIM 606170). More recently, the clinical spectrum of KAT6B disorders has expanded and KAT6B disorders have been suggested to consist of a spectrum of disorders with intermediate and overlapping clinical manifestations. Pathogenic variants in KAT6B mainly occur de novo, with only 3 reports of inherited variants. Here, we describe clinical and molecular findings in a three-generation Danish family with a segregating, previously unreported, pathogenic KAT6B variant. The variant is associated with a phenotype not otherwise specified (neither SBBYSS nor GPS) and with variable expressivity, adding further evidence that KAT6B disorders should be seen as a broad clinical spectrum. Furthermore, we highlight the existence of intra-familial variability and that pathogenic variants in KAT6B can be inherited from mildly affected parents.
Hexasomy of the 15q11q13 region: a detailed report and review of the literature.
Chan CYZ, Baker EK, Francis D … +2 more , Milner K, Amor DJ
Eur J Med Genet · 2025 Aug · PMID 40441420 · Publisher ↗
Hexasomy of the Prader-Willi/Angelman Syndrome Critical Region (PWASCR; chromosome 15q11-q13) is very rare with only 13 patients being described to date. The region is known for its high susceptibility to genomic rearran...
Hexasomy of the Prader-Willi/Angelman Syndrome Critical Region (PWASCR; chromosome 15q11-q13) is very rare with only 13 patients being described to date. The region is known for its high susceptibility to genomic rearrangements, and extra copies within the region have been shown to be associated with distinct but variable clinical features of intellectual disability, epilepsy, global developmental delay amongst others. We present a 10-year-old girl with moderate to severe intellectual disability, cerebral palsy, seizures, autistic features and challenging behaviours. Her karyotype is 47,XX,+mar[25]/46,XX[5]. On chromosome analysis using G-banding, we identified a very large dicentric supernumerary marker chromosome 15q11-q13. Microarray analysis and metaphase fluorescence in-situ hybridisation using the SNRPN gene specific to 15q11.2-q13.3 region showed 87 % of cells containing 6 signals and 13 % of cells containing 2 signals. This represents mosaicism for a partial hexasomy of the long arm of chromosome 15q. We also reviewed and consolidated the literature of all reported patients with hexasomy of PWASCR, and found that amongst all 14 patients (including ours), despite some variation in phenotype, all patients had seizures, and the majority had intellectual disability and challenging behaviours.
RHOA-associated disorder can be non-mosaic.
Nakato D, Morisada N, Iwatani S … +7 more , Nishida C, Watanabe D, Yamada M, Suzuki H, Miya F, Kosaki K, Takenouchi T
Eur J Med Genet · 2025 Jun · PMID 40414526 · Publisher ↗
Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic...
Recurrent somatic mosaic pathogenic variants of RHOA have been observed in a newly identified neuroectodermal syndrome, Ectodermal Dysplasia with Facial Dysmorphism and Acral, Ocular, and Brain Anomalies, Somatic Mosaic [EDFAOB]. All 12 previously reported patients had somatic mosaicism for RHOA variants. Conversely, no patients with non-mosaic germline variants of RHOA have been reported. The absence of non-mosaic patients has been explained by the presumed lethal effect of all RHOA variants in non-mosaic status. Here we report an 11-month-old female with EDFAOB-like features but without Blaschko's skin lesions or asymmetry. Characteristic features included hypertelorism, 2-3 toes cutaneous syndactyly, cleft palate and duplicated uterus and kidney malformations. She carried the non-mosaic de novo germline variant RHOA:c.202C>A,p.(Arg68Ser) near the hotspot in the switch II region in peripheral blood and buccal swabs. The documentation of a living patient with a non-mosaic germline variant of RHOA negates the previous notion that patients with RHOA variants are not viable. The differential diagnosis of a "non-mosaic" RHOA-related disorder would include Ectodermal Dysplasia-Ectrodactyly-Clefting syndrome, as both conditions share ectodermal dysplasia, finger anomalies, and clefting. This phenotypic similarity may be explained by the known molecular interaction between TP63, the gene responsible for EEC syndrome, and RHOA. RHOA is a member of the RAC subfamily of small Rho family guanosine triphosphatases, which include RHOA, RAC1, RAC3, and CDC42 (Takenouchi-Kosaki syndrome). The documentation of germline RHOA-associated intellectual disability in the present article establishes that variants in all three genes of the RAC subfamily of small Rho family GTPases are associated with neurodevelopmental disorders.
Management of a case of melorheostosis deformity and pain with intramedullary nailing.
Ruzzini L, Gonfiantini MV, Asunis E … +3 more , Ubertini GM, Bartuli A, Costici P
Eur J Med Genet · 2025 Jun · PMID 40383483 · Publisher ↗
Melorheostosis is a rare sclerosing bone dysplasia characterized by the thickening and irregular ossification of the affected bones. This disease can affect any bone in the skeletal system, with the long bones of the low...
Melorheostosis is a rare sclerosing bone dysplasia characterized by the thickening and irregular ossification of the affected bones. This disease can affect any bone in the skeletal system, with the long bones of the lower extremities being more frequently involved. Symptoms include pain, oedema, joint stiffness, muscle atrophy and bone deformity. Management of this disease is challenging and not standardized. It depends on the symptoms, and it varies from physical therapy to pharmacological approach or surgery to correct limb deformities, muscle and tendon contractures and joint stiffness. This case report presents the clinical management and treatment of a patient with lower limb deformities due to melorheostosis using retrograde intramedullary nailing of the femurs. The procedure provided stability to the affected bones, resulting in correction of deformities and alleviation of lower limb pain, improving her quality of life.
Comparison of bilateral tibial lengthening with circular external fixator and simultaneous deformity correction with hexapod external fixator in Achondroplasia.
Bocchi MB, Palmacci O, Vitiello R … +3 more , Giuli C, Ziranu A, Maccauro G
Eur J Med Genet · 2025 Jun · PMID 40306613 · Publisher ↗
Achondroplasia is a growth plate dysplasia caused by FGFR-3 gene mutation. In addition to dysmorphic short stature, genu varum is very common. Therefore, a certain part of the achondroplasic population is interested in e...
Achondroplasia is a growth plate dysplasia caused by FGFR-3 gene mutation. In addition to dysmorphic short stature, genu varum is very common. Therefore, a certain part of the achondroplasic population is interested in extensive cosmetic limb lengthening and deformity correction to achieve a functional height so that they can attain total autonomy in everyday life. All patients who underwent bone lengthening treatment from March 2014 to December 2022, were retrospectively analyzed in terms of inclusion and exclusion criteria. To determine any angular deformity in the coronal plane, the Mechanical Axis Deviation was calculated. Patients were divided into two groups: group A included patients who had no angular deformity and therefore performed exclusively cosmetic bilateral tibial lengthening, group B included patients undergoing cosmetic lengthening and simultaneous bilateral multiplanar correction of tibial deformities with hexapod external fixator. The achieved distraction, the external fixator index and the consolidation index were calculated and compared for the two groups. Any adverse event was recorded. According to inclusion and exclusion criteria, 14 patients (28 tibias) diagnosed with Achondroplasia were included (20 tibias group A and 8 tibias group B). We found a statistically significant difference between the two groups regarding the mean age at the time of surgery (p 0.01). The mean MAD value within group B showed a substantial improvement from 56.50 ± 19.1 mm to 14.6 ± 5 mm. Comparing the two groups, we observed a statistically significant difference between both preoperative (p 0.0001) and postoperative (p 0.006) MAD values. The difference found between the two groups was significant also in terms of mean external fixator index (35.9 days/cm versus 52.5 days/cm) and consolidation index (24.2 days/cm versus 37.9 days/cm). Comparing the adverse events found in the two groups no significant differences emerged (p 0.7). In the context of cosmetic lower limb lengthening program for achondroplasic patients, most studies have focused on linear lengthening often underestimating the importance of any associated deformities correction. In our experience, the genu varum correction with the hexapod system showed relevant results in term of MAD improvement. Our results show a significant difference between the two groups in consolidation (p 0.002) and thus also in external fixation (p 0.001) time to the disadvantage of the hexapod group probably due to: higher age (p 0.01) with lower healing potential, greater difficulty in weightbearing and in dynamizing the fixator.
Diagnostic delays in rare genetic disorders with neuropsychiatric manifestations: A systematic review.
Siegel IJ, Vaithilingam SL, Hartig MM … +3 more , Patty EC, Mantsch LE, Garrison SR
Eur J Med Genet · 2025 Jun · PMID 40252994 · Publisher ↗
A systematic review of case reports, case series, and case-control studies was conducted to quantify the diagnostic delay in 84 rare genetic diseases where neuropsychiatric symptoms may be primary or part of the early cl...
A systematic review of case reports, case series, and case-control studies was conducted to quantify the diagnostic delay in 84 rare genetic diseases where neuropsychiatric symptoms may be primary or part of the early clinical presentation. Data abstracted from 1221 published articles encompassing 1838 individual cases revealed a mean diagnostic delay of 9.3 ± 8.7 years, with no significant improvement in time to diagnosis over the 65-year period from 1958 to 2023. Subanalysis of the most recent 10 years, 2014-2023, revealed no change in diagnostic delay, even when stratifying by genetic and other diagnostic tests. Neuropsychiatric symptoms were reported in 68 % of the included cases. Following a definitive diagnosis and optimized management of the underlying rare genetic disease, 66 % of individuals experienced an improvement in their neuropsychiatric symptoms. Despite increasing access to, and substantial advancement in, genetic and other testing, diagnostic delays remain lengthy for individuals affected by these rare genetic diseases. This often results in suboptimal management of the associated neuropsychiatric symptoms. Thus, earlier implementation of genetic testing and other diagnostic tools may reduce these delays, improving patient outcomes and alleviating the burden of diagnostic uncertainty.
Evaluating parental satisfaction and empowerment with genetic testing in the Neonatal Intensive Care Unit (NICU).
Kim S, Osiovich H, Langlois S … +4 more , Virani A, Shen Y, GenCOUNSEL Study, Elliott AM
Eur J Med Genet · 2025 Jun · PMID 40194738 · Publisher ↗
Genetic disorders are highly represented in the neonatal intensive care unit (NICU). Genetic testing (in particular rapid genome-wide sequencing) has transformed the ability to diagnose and manage these infants. The NICU...
Genetic disorders are highly represented in the neonatal intensive care unit (NICU). Genetic testing (in particular rapid genome-wide sequencing) has transformed the ability to diagnose and manage these infants. The NICU is a place of stress and overwhelm for parents and implementing genetic testing can pose additional challenges, including anxiety. There is a critical gap in knowledge related to parents' empowerment and satisfaction with the NICU experience for those undergoing genetic testing. The goal of this mixed-methods study was to identify the key contributing factors related to empowerment and areas for improvement in care of parents undergoing genetic testing in the NICU by using validated tools that have not been previously implemented in Canada. A demographic survey and validated online survey tools were distributed to eligible parents. Descriptive statistics and linear regression analysis were performed. We conducted semi-structured interviews to gain insight into the genetic testing experience. The transcribed interviews were analyzed using an interpretive description framework and thematic analysis. A total of 31 surveys and 17 interviews were completed. We have identified self-reported demographic predictors of decreased satisfaction and empowerment for parents, including high income, English-speaking, ethnicity, sex of the parent, prematurity of the newborn, and length of hospital stay. Emerging themes from interviews fall under the broad category of communication and include information, logistics, parental perspective, and support. Subthemes include expectations and delivery of information, attention to timing and organization, comprehensive support, and parental distress and expectations when ordering genetic testing. The findings suggest the need for systematic improvement of the current genetic testing process in NICUs.
Familial inheritance of 14q terminal deletion syndrome and review of the literature.
Vincent KM, Prince B, McGowan-Jordan J … +1 more , Carter MT
Eur J Med Genet · 2025 Jun · PMID 40180153 · Publisher ↗
Terminal deletions of chromosome 14q are characterized by a spectrum of phenotypes that can include microcephaly, growth deficiency, intellectual disability, characteristic facial features, and various congenital anomali...
Terminal deletions of chromosome 14q are characterized by a spectrum of phenotypes that can include microcephaly, growth deficiency, intellectual disability, characteristic facial features, and various congenital anomalies. The rarity of this syndrome, together with the broad spectrum of phenotypes, has made genotype-phenotype correlations difficult. Herein, we describe a family with the core features of the condition and a heterozygous 3.7 Mb deletion at 14q32.32qter. To our knowledge, this is the first case of vertical transmission of a terminal 14q deletion. In addition to this family, we review 19 previously reported individuals. Additional descriptions of individuals with terminal 14q deletions will help to fully characterize the phenotypic spectrum and define the natural history of this condition.
A rare triplication of 16p11.2: Unravelling the genomic complexity and review of the literature.
van der Laan L, Kleinendorst L, Haagmans MA … +5 more , Roquas L, van der Smagt JJ, Koop K, Henneman P, van Haelst MM
Eur J Med Genet · 2025 Jun · PMID 40180152 · Publisher ↗
16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.2 tripl...
16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.2 triplication, whose healthy father has a smaller 16p11.2 duplication that partially overlaps with that of the daughter. She has a global developmental delay, autism spectrum disorder, anxiety, and sensory processing issues, alongside dysmorphic features. Genetic analysis revealed triplication within the 16p11.2 duplication region. We used different technical approaches to pinpoint the exact genetic architecture of the triplication and to gain further functional insights. Using array-CGH and Fluorescence In Situ Hybridization (FISH), we detected the location of the triplication. We later sought to confirm this with Oxford Nanopore Technologies (ONT); however, detecting duplications and triplications proved to be challenging. Finally, RNA sequencing showed overexpression of genes within the triplication region, including INO80E, PAGR1, SPN, KIF22, HIRIP3, TAOK2, and TMEM219, some of which had been associated with neurodevelopmental disorders and/or increased body mass index by GWAS (1). Our findings contribute to the understanding of the phenotypic spectrum and molecular mechanisms of 16p11.2 triplication. Moreover, the challenges in detecting triplications using current sequencing methods highlight the need for improved diagnostic techniques.
Lack of behavioural improvement with sirolimus in a patient with MTOR-related macrocephaly with pigmentary mosaicism: A new case report.
Bonniaud B, Luu M, Cormier C … +12 more , Racine C, Espitalier A, Malbranche C, Rega A, Gaumet T, Kuentz P, Vabres P, Thauvin-Robinet C, Bardou M, Gay S, Faivre L, Delanne J
Eur J Med Genet · 2025 Jun · PMID 40127731 · Publisher ↗
Postzygotic activating MTOR variants result in neurocutaneous mosaic phenotypes including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism (hypomelanosis of Ito), whereas germline activating variants ca...
Postzygotic activating MTOR variants result in neurocutaneous mosaic phenotypes including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism (hypomelanosis of Ito), whereas germline activating variants cause Smith-Kinsgmore syndrome. The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. As rapamycin downregulates the increased activity caused by the mosaic mTOR variant, it may result in improvement of clinical outcomes, as shown for refractory epilepsy in tuberous sclerosis, another genetic disease of the mTOR pathway. However, results of treatment have been reported in only three genotyped patients so far, one with pigmentary mosaicism, megalencephaly and epilepsy, and two with focal cortical dysplasia, with conflicting results. Here we report on a 12-year-old male patient with megalencephaly-pigmentary mosaicism and a mTOR mosaic gain-of-function variant (p.(Ser2413Ile)) in 23 % of affected skin cells, who received compassionate off-label sirolimus for severe behavioural disorder. Sirolimus was initiated at 1.3 mg twice a day with regular blood monitoring. After a 6-months period, no improvement was observed, neither on family environment-reported outcomes nor on neuropsychology scales, leading to treatment discontinuation. Despite physiopathological rationale, case reports have failed so far to suggest efficacy on the outcomes studied, which questioned the implementation of clinical trials.
Identifying patients with neurofibromatosis type 1 related optic pathway glioma using the OMOP CDM.
Dhaenens BAE, Moinat M, Didden EM … +3 more , Ammour N, Oostenbrink R, Rijnbeek P
Eur J Med Genet · 2025 Jun · PMID 40107446 · Publisher ↗
Neurofibromatosis type 1 (NF1) is a rare tumour predisposition syndrome. Optic pathway gliomas (NF1-related OPG) are a well-characterised tumour type. There is great need for tools that can efficiently identify patients...
Neurofibromatosis type 1 (NF1) is a rare tumour predisposition syndrome. Optic pathway gliomas (NF1-related OPG) are a well-characterised tumour type. There is great need for tools that can efficiently identify patients with NF1-related OPG at hospitals. Computable phenotypes algorithms can be used to find patients with certain clinical features in an electronic database. We developed computable phenotype algorithms using the Observational Medical Outcome Partnership (OMOP) Common Data Model. We subsequently assessed if these algorithms could identify patients with NF1-related OPG in an electronic health records (EHR) derived database. We created phenotype algorithms based on diagnosis codes, visits, and radiologic procedures. These phenotypes were applied to the EHR-derived database of an academic hospital. To assess the performance of the phenotypes, we calculated the precision, recall, and F2 score against a list of known cases (n = 61), provided by a clinician. To evaluate the ability of the phenotypes to identify additional cases, we manually reviewed the predicted positives of each phenotype algorithm. The phenotype algorithm based on the diagnosis codes 'Neurofibromatosis syndrome' and 'Neoplasm of optic nerve' performed best (precision = 1.000, recall = 0.614, F2-score = 0.665). The phenotype 'Neurofibromatosis syndrome and three or more Ophthalmology visits and one or more MRI of brain' performed best of the phenotypes based on visits and radiologic procedures (precision = 0.489, recall = 0.511, F2-score = 0.507). Generally, increased precision came at the cost of a decrease in recall. Following review of the predicted positives of each phenotype, 27 additional cases were identified. OMOP computable phenotype algorithms successfully identified NF1-related OPG patients in an EHR-derived database. They provided swift insight into the number of NF1-related OPG cases and were able to identify additional cases, which were not included in the original list of known cases. Phenotype algorithms created with OMOP could be an invaluable tool to facilitate patient screening, especially in multi-centric trials for rare diseases.
The craniofacial, dental and systemic manifestations of Enamel Renal Syndrome: A Scoping review.
Roomaney IA, Kabbashi S, Chetty M
Eur J Med Genet · 2025 Jun · PMID 40089179 · Publisher ↗
INTRODUCTION: Enamel Renal Syndrome (ERS) (OMIM 204690) is a rare genetic condition characterised by a distinct oral profile and sometimes nephrocalcinosis. This autosomal recessive condition, caused by pathogenic varian...
INTRODUCTION: Enamel Renal Syndrome (ERS) (OMIM 204690) is a rare genetic condition characterised by a distinct oral profile and sometimes nephrocalcinosis. This autosomal recessive condition, caused by pathogenic variants in the FAM20A gene, is linked to ectopic mineralisation in tissues such as dental pulp, follicles, gingiva, and kidneys. Although the oral phenotype has been well-characterised, less common features have been described, highlighting possible gaps in the literature on the phenotypic variability of the condition. METHODS: This scoping review follows PRISMA-ScR guidelines and aimed to synthesise existing literature on ERS, focusing on clinical and radiographic features, oral histology, systemic manifestations, and molecular findings. A comprehensive search was conducted in multiple databases, with inclusion criteria broad enough to capture relevant studies under various nomenclatures. The screening process involved independent review and data extraction with a custom tool. RESULTS: The initial search yielded 430 references, supplemented by additional publications identified through Google Scholar and citation searching. After removing duplicates and resolving inter-rater discrepancies, 62 studies were included, encompassing a diverse global sample. Publications spanned from the first report in 1972 to recent studies in 2024. The included studies highlight the characteristic oral profile of ERS and less consistently reported renal manifestations. While the pathognomonic oral profile remains consistent, long-term studies are required to fully understand renal and systemic impacts. Current management strategies are patient-specific, with a need for standardised reporting and long-term follow-up to develop evidence-based guidelines. Until more comprehensive data is available, vigilant monitoring of kidney function in ERS patients remains essential. CONCLUSION: This review confirms that ERS presents with a distinct oral and dental profile. However, inconsistencies in the reporting of craniofacial, renal, and other systemic features were noted. To improve patient care, further research is essential to better understand the systemic implications and long-term outcomes of ERS. This will support the development of evidence-based guidelines and foster a more holistic approach to managing the condition.
Isolated congenital vertebral anomaly and Sprengel's deformity in a WBP11 pathogenic variant.
Shin BK, Kim J, Kim MS … +1 more , Jang DH
Eur J Med Genet · 2025 Jun · PMID 40089178 · Publisher ↗
The pathogenic variant of WBP11 has been known as one of the various genetic causes of VACTERL syndrome. VACTERL syndrome is usually diagnosed with at least three clinical features of vertebral, heart, tracheal, esophage...
The pathogenic variant of WBP11 has been known as one of the various genetic causes of VACTERL syndrome. VACTERL syndrome is usually diagnosed with at least three clinical features of vertebral, heart, tracheal, esophageal, kidney, and limb anomalies. So far, only four WBP11 pathogenic variants have been documented from 13 patients, first and latest described in 2020. In this clinical report, we present a patient with an isolated vertebral anomaly and Sprengel's deformity, carrying a pathogenic variant of WBP11, representing a distinctive case of patient that has never been described before. An eight-month-old boy with a 5°-10° head tilt to the right was referred to our institution and the cervical X-ray imaging showed the vertebral anomaly. Three-dimensional (3D) volume-rendered computed tomography (CT) of the cervical spine revealed the fusion state of the right C2 and C3 facet joints. And the right shoulder appeared to be raised and right scapula elevation was identified in the 3D chest CT. In addition, whole genome sequencing presented a de novo novel WBP11 heterozygous pathogenic variant, with frameshift resulting in a loss of function. WBP11 is a cell cycle-related pleiotropic gene that encodes a pre-messenger RNA splicing factor involved in centriole duplication. Pathogenic variants in WBP11 are genetically implicated in the development of multiple congenital anomalies. Clinically, WBP11 has been previously associated with VACTERL syndrome. In this report, we document clinical manifestations, including vertebral anomalies and Sprengel's deformity. The findings presented in this report indicate that haploinsufficiency of WBP11, resulting from a heterozygous pathogenic variant, may give rise to a more diverse array of clinical phenotypes than previously documented.
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