Marini C, Rosati A, Fusco L, Mastrangelo M, Izzo F, Olivotto S, Siliquini S, Cordelli DM, Mondardini MC, Vittorini R, Conio A, Battaglia DID, Pulitanò SM, Striano P, Riva A, Sartori S, Tona C, Darra F, Proietti J, Zanus C, Costa P, Parrini E, Guerrini R, Vigevano F, Bartolotta P; Italian Pediatric Status Epilepticus (IPSE) Group. Genetic Etiologies of Epilepsies With Status Epilepticus: Insights From the Italian Pediatric Status Epilepticus Group Cohort. Neurology. 2026 Apr 28;106(8):e214791. doi: 10.1212/WNL.0000000000214791. Epub 2026 Mar 31. PMID: 41915870.
Abstract
Background and objectives: Genetic factors are major contributors to pediatric epilepsy, but their role in status epilepticus (SE) remains incompletely defined. We aimed to characterize the clinical and genetic landscape of pediatric epilepsy complicated by SE in a large cohort, and to identify clinical features associated with genetic etiologies.
Methods: We conducted a retrospective, multicenter, exploratory cohort study by selecting patients aged 1 month-18 years who experienced SE from the Italian Pediatric Status Epilepticus (IPSE) group database (2010-2022). SE and epilepsy syndromes were defined according to International League Against Epilepsy criteria. From the IPSE dataset, we included only patients with epilepsy whose etiology was classified as genetic (confirmed or presumed) or nongenetic (lesional, autoimmune, metabolic-acquired, infectious, or unknown). Clinical data were collected using standardized electronic case report forms.
Results: Of 1,071 children in the IPSE cohort, 790 with SE and epilepsy were included (median age at SE onset 3.9 years, interquartile range 1.3-8.1; 44% female). A genetic etiology was confirmed or presumed in 519 (66%). Compared with those with nongenetic etiologies (n = 271), patients with genetic epilepsies presented with SE at a younger age (median 3.4 vs 4.8 years, q = 0.003) and more often had epilepsy with both focal and generalized seizures (31% vs 13%, q < 0.001). The underlying genetic abnormality was identified in 222 patients (42.7%) including 179 with confirmed single-gene pathogenic variants and 43 chromosomal alterations. Ion channel genes were most frequent (38%), with SCN1A variants accounting for 18% of confirmed single-gene cases. Neurodevelopmental and mTOR pathway genes were also frequent contributors. Logistic regression showed that younger age at SE (odds ratio [OR] 0.92, 95% CI 0.85-0.98, p = 0.020) and epilepsy with both focal and generalized seizures (OR 4.00, 95% CI 2.09-7.85, p < 0.001) were independently associated with channelopathies.
Discussion: In this large real-world cohort, two-thirds of children with epilepsy and SE had a genetic etiology, most commonly channelopathies. Younger age at SE and epilepsy with both focal and generalized seizure were linked to genetic causes. Despite limitations in testing strategies and retrospective design, these findings highlight the importance of systematic genetic investigation in pediatric epilepsies presenting SE.
Wednesday, April 15, 2026
A lupus story
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Doctors Thought This Mother Had Everything From Ringworm to Leukemia. After 19 Years She Was Finally Diagnosed with Lupus
"I always knew something was wrong with me," says Nyobie Gordon-Ricks, a mom of two
By Wendy Grossman Kantor Published on April 15, 2026 09:15AM EDT
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Doctors Thought it was Ringworm or Leukemia: After 19 Years She Was Diagnosed with Lupus
Nyobie Gordon-Ricks.
Credit : courtesy of Nyobie Gordon-Ricks
Nyobie Gordon-Ricks spent 19 years having her symptoms dismissed or misdiagnosed with everything from ringworm to leukemia before she was diagnosed with lupus in 2010.
“For years, I went to doctors and nobody listened to me,” says Nyobie Gordon-Ricks, 48 of Gilbert, Arizona, who works as a pharmacy technician. “I felt like no one understood and no one believed that there was really something wrong with me.”
Her long path to diagnosis isn’t unusual, says Dr. George Tsokos, a member of the Lupus Foundation of America Medical-Scientific Advisory Council, who has spent years educating healthcare professionals about the symptoms and signs of lupus, an autoimmune disease which attacks the body's own tissue. Because lupus can present in many different ways, symptoms can range from headaches and fatigue to joint paint to hair loss to seizures, which means that no two people might experience it the same way — and thus it can often be overlooked as a diagnosis.
“A big problem is, even in great medical centers, sometimes it takes a lot of time to diagnose,” says Tsokos, who is also chief of rheumatology and clinical immunology at Beth Israel Deconess Medical Center and professor at Harvard Medical School. “If there are symptoms that are not explained, insist on getting more expert opinions and find people who can treat early and treat aggressively.”
Now an ambassador for the Lupus Foundation of America, Gordon-Ricks shares her story urging others to advocate for themselves and to know they are not alone as they battle lupus, a misunderstood and often invisible illness.
“I want people to know that you have to look beyond what's visible. This disease is a disease that nobody can see,” she says.
Gordon-Ricks says her symptoms started when she was 13. Her knees and ankles were swollen, her back hurt and she had a rash on her face.
Her mother took her to a doctor who dismissed it as hormonal changes from puberty.
A year later, she started having episodes of partial paralysis. “I would go numb from my waist down,” she recalls. “I told my mom and she thought I was being lazy and I didn't want to go to school. I would literally lay on our living room floor for hours, waiting for the feeling to come back.”
The second time the paralysis happened, her mother called an ambulance. At the hospital, she was categorized as having a “mental episode,” she says. She was hospitalized for two days, then released: “After that I was like, “I'm just not going to tell anybody anything anymore because nobody's believing me."
She experienced partial paralysis throughout high school, she says, and would wait out the episodes with a heating pad and pain medications.
“There were days where I felt well, and then there were days where I wasn't,” she says. “I didn't know what was going on with me."
In 2009, she got a rash on her back, arms and legs; the first dermatologist she saw said she had ringworm. The second doctor thought it didn’t look like ringworm, but didn't have a better suggestion. Steroid cream helped and the rash went away, but Gordon-Ricks wanted to know what was wrong. She was, 32, engaged and planning her wedding.
In May 2010, she told her gynecologist about her symptoms; bloodwork showed her platelets and red and white blood cells were all low. She saw a series of doctors who thought she might have leukemia, multiple sclerosis or rheumatoid arthritis. The sixth specialist she visited asked if anyone in her family had lupus. She said no.
On December 11, 2010, she learned she tested positive for lupus. It was five days before her 33rd birthday.
“I'm feeling a little bit of relief because now I know what's wrong with me, but now I'm scared because I don't know what this means for me,” she says.
Her fiancé told her she would be fine. His aunt had lupus, and she always seemed fine, he said.
“I said, ‘From what I understand, a person can look fine but still be sick. Right now, I know physically I look good. But I feel like crap. Everything is sore. Everything hurts. When I move, it hurts,’ ” she recalls.
The unpredictability also meant she needed help caring for her then-3-year-old daughter and 8-year-old son.
“I went from wrestling with my kids to it hurting just for one of them to hug me,” she says. “I was in bed for days because the furthest I could go was from my bedroom to my bathroom. I couldn't comb my hair. I could barely brush my teeth. It was a hard adjustment because you're looking at somebody who on the outside looks healthy, but the inside their body is falling apart.”
She took her mother or her fiancé with her when she went to the doctor, because she had trouble remembering what the doctor told her.
“I was really spacey,” she says. “I could be in the middle of a conversation and I'll just stop talking because I lose train of thought.”
Plus she was having terrible headaches. “It felt like I can feel a heartbeat in my skull, all like the thump. I don't know what's going on,” she says.
https://people.com/lupus-diagnosis-after-years-of-misdiagnosis-exclusive-11919604
Her doctor ordered a full body scan. “He said, ‘You have inflammation from your brain to your toes. There is some type of swelling in every single part of your body,' " she recalls. The diagnosis: Lupus cerebritis, which affects the brain.
“I was scared for my life,” she recalls: “Can I die from this? Is this something that's fatal? How treatable is it?”
In March 2012, she started 12 rounds of monthly chemotherapy, which was effective.
And when she returned to the gynecologist who first took her symptoms seriously, Gordon-Ricks was emotional. "I told her, 'You literally saved my life. It's in my kidneys, it’s attacking my joints, and it's in my brain.’ She just hugged me and I cried like a baby. I was like, 'I don't think that I would be here if you didn't listen to me.' "
When Gordon-Ricks finished chemo, she and her fiancé moved to Arizona and got married in March 2014. “He’s been a big support. He goes to the doctor with me. He asks questions that I may not ask. He recognizes when I'm not feeling well, even when I pretend that I'm okay. He's even helped me facilitate lupus support groups. He was able to step in and help me the way that I needed help,” she says.
Her lupus nephritis went into remission in 2017. Because the lupus attacked her ovaries, cervix, and fallopian tubes, she had a full hysterectomy in September 2018.
Today, her lupus is still active, but is controlled by medication. She actively volunteers with the Lupus Foundation as an ambassador, speaking at health fairs and spreading awareness. She shares her story in hopes it will help other people get diagnosed more quickly than she did. She runs her own lupus awareness website, the Arizona Butterfly Warriors, and is active on social media.
“The biggest advice I can give is: Never give up. Learn how to be an advocate for yourself. Learn how to ask for a second opinion. Never take no for an answer. If you feel like you're not being heard, if you feel like your doctor isn't listening, find a new doctor,” she says. “If you know in your heart something's wrong with you, you need to keep going until you get the answers that you deserve. There is hope: There are people that are willing to listen. You just have to find them.”
A lupus diagnosis, she says, is not a death sentence.
“We can survive this,” she says.
https://people.com/lupus-diagnosis-after-years-of-misdiagnosis-exclusive-11919604
Sunday, April 12, 2026
Why only boys or girls sometimes runs in the family
Women who have had multiple children of the same sex are more likely to have another baby of the same sex, a new study has found.
Maternal age and genetics could be ‘weighting the coin toss’ for some couples, rather than every child having a truly random 50/50 chance of being a boy or a girl.
The study also showed that older mothers were more likely to have children of the same sex, and revealed two genes that could increase the likelihood of having all female or all male children, respectively.
A child’s sex at conception is determined by whether the sperm carries an X or Y chromosome, which should mean it’s a perfect coin flip over whether a child will be a boy or a girl.
However, PhD student Siwen Wang from Harvard University noticed this didn’t always seem to be the case.
“This project actually began with casual conversations among co-authors and friends about families we knew who had all boys or all girls,” said Wang to BBC Science Focus.
“It came up often enough that we started wondering: is it really just chance? Or is there a biological reason some families keep having children of the same sex?”
Wang and her colleagues drew on information from more than 58,007 women who had given birth to two or more children, checking if there were more families with siblings of all the same sex than you might expect due to random chance.
They found that if a couple had already had three boys, they had a 61 per cent chance of having another boy. Similarly, there was a 58 per cent chance of having another girl after having three girls.
The study identified a few factors that potentially tipped the scales in favour of all girl or all boy families.
“Women who had their first child after age 28 had about a 10 per cent higher chance of having only boys or only girls, compared to those who started before age 23,” said Wang. “So it’s not a huge shift, but it’s statistically significant.”
Though the study didn’t look into what might be causing this link, Wang did speculate on a few theories.
“As women age, they experience physiological changes such as shorter follicular phase and lower vaginal pH,” she said.
The follicular phase is the first stage of the menstrual cycle and tends to favour the survival of Y-chromosome sperm. Lower vaginal pH, however, favours X-chromosome sperm.
“These effects may differ from woman to woman, so ageing may tip the balance toward one sex or the other, depending on their specific biology,” said Wang.
Wang also suggested another possible connection.
“Older maternal age is usually highly associated with older paternal age. But unfortunately, we did not have paternal data to explore this aspect in our study," said Wang.
The researchers were also able to obtain genetic information for 7,530 women included in the study, looking for any relevant genetic markers. They found two – SNP NSUN6, which was associated with all female offspring; and SNP TSHZ1, which correlated to all male.
Wang also looked into whether behavioural factors could be creating such runs of single-sex children, such as couples who keep having boys continuing to have children until they have a girl, and vice versa.
“We ran analyses where we excluded the last birth in each family, which is the one most likely to be influenced by parents stopping once they’ve had both a boy and a girl. Even after doing that, we still see strong same-sex clustering,” said Wang.
About our expert
Siwen Wang is a PhD student in Nutritional Epidemiology at Harvard T.H. Chan School of Public Health. She investigates how nutrition, lifestyle, and psychosocial factors affect maternal and child health.
https://www.sciencefocus.com/news/boys-girls-birth
Maternal age and genetics could be ‘weighting the coin toss’ for some couples, rather than every child having a truly random 50/50 chance of being a boy or a girl.
The study also showed that older mothers were more likely to have children of the same sex, and revealed two genes that could increase the likelihood of having all female or all male children, respectively.
A child’s sex at conception is determined by whether the sperm carries an X or Y chromosome, which should mean it’s a perfect coin flip over whether a child will be a boy or a girl.
However, PhD student Siwen Wang from Harvard University noticed this didn’t always seem to be the case.
“This project actually began with casual conversations among co-authors and friends about families we knew who had all boys or all girls,” said Wang to BBC Science Focus.
“It came up often enough that we started wondering: is it really just chance? Or is there a biological reason some families keep having children of the same sex?”
Wang and her colleagues drew on information from more than 58,007 women who had given birth to two or more children, checking if there were more families with siblings of all the same sex than you might expect due to random chance.
They found that if a couple had already had three boys, they had a 61 per cent chance of having another boy. Similarly, there was a 58 per cent chance of having another girl after having three girls.
The study identified a few factors that potentially tipped the scales in favour of all girl or all boy families.
“Women who had their first child after age 28 had about a 10 per cent higher chance of having only boys or only girls, compared to those who started before age 23,” said Wang. “So it’s not a huge shift, but it’s statistically significant.”
Though the study didn’t look into what might be causing this link, Wang did speculate on a few theories.
“As women age, they experience physiological changes such as shorter follicular phase and lower vaginal pH,” she said.
The follicular phase is the first stage of the menstrual cycle and tends to favour the survival of Y-chromosome sperm. Lower vaginal pH, however, favours X-chromosome sperm.
“These effects may differ from woman to woman, so ageing may tip the balance toward one sex or the other, depending on their specific biology,” said Wang.
Wang also suggested another possible connection.
“Older maternal age is usually highly associated with older paternal age. But unfortunately, we did not have paternal data to explore this aspect in our study," said Wang.
The researchers were also able to obtain genetic information for 7,530 women included in the study, looking for any relevant genetic markers. They found two – SNP NSUN6, which was associated with all female offspring; and SNP TSHZ1, which correlated to all male.
Wang also looked into whether behavioural factors could be creating such runs of single-sex children, such as couples who keep having boys continuing to have children until they have a girl, and vice versa.
“We ran analyses where we excluded the last birth in each family, which is the one most likely to be influenced by parents stopping once they’ve had both a boy and a girl. Even after doing that, we still see strong same-sex clustering,” said Wang.
About our expert
Siwen Wang is a PhD student in Nutritional Epidemiology at Harvard T.H. Chan School of Public Health. She investigates how nutrition, lifestyle, and psychosocial factors affect maternal and child health.
https://www.sciencefocus.com/news/boys-girls-birth
Tuesday, April 7, 2026
CACNA1E mutation
Kayleigh and Ryan Dunn’s 11-month-old daughter, Lorelei, was diagnosed with CACNA1E. Due to this neurological condition, she lives with mobility challenges, experiences frequent seizures and requires a feeding tube.
Patrick Lawlor, Lorelei's neurologist in Michigan, described the severity of CACNA1E to local news outlet WXYZ, saying, “The lack of progress is something that really signals how severe her disorder is. Probably one of the most severe children I’ve taken care of. She has clusters of brief seizures. Sometimes 10 or 20 times per day.”
The Michigan mom explained that it's “even harder” because Lorelei has “no head control or upper body control.” Kayleigh added, "Even though we’re desensitized. It breaks my heart to see her like this."
Kayleigh has been documenting Lorelei's health journey on TikTok, inciting an outpouring of love and support, including when she had a G-tube surgery in January.
"She took it like a champ, and I could not be prouder of her," Kayleigh captioned the TikTok video. "I cannot wait to get her home and comfortable in her own bed. But for now, I’m going to enjoy this quiet moment alone in our little hospital room, just the two of us."
Kayleigh told WXYZ that Lorelei, who enjoys bath time, is nonverbal, adding, “For someone who is nonverbal, she is very vocal.”
The mother is hopeful that their family’s story encourages other people to get tested for neurological conditions.
Angela Munaco, one of the family’s close friends set up a GoFundMe to help the family cover Lorelei's medical bills and other costs.
“Shortly after her diagnosis, Kayleigh’s husband [Ryan] suffered a serious back injury at work, leaving him unable to work for several months,” the GoFundMe said. “Between his recovery, endless doctor appointments, and the long wait for state approval of Lorelei’s special needs insurance, Kayleigh had no choice but to step back from full-time work. She now works part-time when she can, balancing her career with being Lorelei’s full-time caregiver.”
Kayleigh told WXYZ, “I just want [Lorelei] to know I tried everything I can to make her better.”
Lexi Lane
https://people.com/michigan-girl-diagnosed-with-rare-genetic-disorder-cacna1e-11940319
Di Micco V, Affronte L, Khinchi MS, Rønde G, Miranda MJ, Hammer TB, Specchio N, Beniczky S, Olofsson K, Møller RS, Gardella E. Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? Epileptic Disord. 2024 Aug;26(4):520-526. doi: 10.1002/epd2.20242. Epub 2024 May 23. PMID: 38780451.
Abstract
Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.
Ortiz Cabrera NV, Duat Rodríguez A, Fernández Garoz B, Bernardino Cuesta B, Jiménez Legido M, Cantarín Extremera V, García Peñas JJ. Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. Mol Syndromol. 2021 Mar;12(1):25-32. doi: 10.1159/000511926. Epub 2020 Dec 10. PMID: 33776624; PMCID: PMC7983621.
Abstract
Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.
Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N; Task Force for Neonatal Genomics; Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study; Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015. PMID: 30343943; PMCID: PMC6216110.
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Patrick Lawlor, Lorelei's neurologist in Michigan, described the severity of CACNA1E to local news outlet WXYZ, saying, “The lack of progress is something that really signals how severe her disorder is. Probably one of the most severe children I’ve taken care of. She has clusters of brief seizures. Sometimes 10 or 20 times per day.”
The Michigan mom explained that it's “even harder” because Lorelei has “no head control or upper body control.” Kayleigh added, "Even though we’re desensitized. It breaks my heart to see her like this."
Kayleigh has been documenting Lorelei's health journey on TikTok, inciting an outpouring of love and support, including when she had a G-tube surgery in January.
"She took it like a champ, and I could not be prouder of her," Kayleigh captioned the TikTok video. "I cannot wait to get her home and comfortable in her own bed. But for now, I’m going to enjoy this quiet moment alone in our little hospital room, just the two of us."
Kayleigh told WXYZ that Lorelei, who enjoys bath time, is nonverbal, adding, “For someone who is nonverbal, she is very vocal.”
The mother is hopeful that their family’s story encourages other people to get tested for neurological conditions.
Angela Munaco, one of the family’s close friends set up a GoFundMe to help the family cover Lorelei's medical bills and other costs.
“Shortly after her diagnosis, Kayleigh’s husband [Ryan] suffered a serious back injury at work, leaving him unable to work for several months,” the GoFundMe said. “Between his recovery, endless doctor appointments, and the long wait for state approval of Lorelei’s special needs insurance, Kayleigh had no choice but to step back from full-time work. She now works part-time when she can, balancing her career with being Lorelei’s full-time caregiver.”
Kayleigh told WXYZ, “I just want [Lorelei] to know I tried everything I can to make her better.”
Lexi Lane
https://people.com/michigan-girl-diagnosed-with-rare-genetic-disorder-cacna1e-11940319
Di Micco V, Affronte L, Khinchi MS, Rønde G, Miranda MJ, Hammer TB, Specchio N, Beniczky S, Olofsson K, Møller RS, Gardella E. Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? Epileptic Disord. 2024 Aug;26(4):520-526. doi: 10.1002/epd2.20242. Epub 2024 May 23. PMID: 38780451.
Abstract
Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.
Ortiz Cabrera NV, Duat Rodríguez A, Fernández Garoz B, Bernardino Cuesta B, Jiménez Legido M, Cantarín Extremera V, García Peñas JJ. Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. Mol Syndromol. 2021 Mar;12(1):25-32. doi: 10.1159/000511926. Epub 2020 Dec 10. PMID: 33776624; PMCID: PMC7983621.
Abstract
Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.
Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N; Task Force for Neonatal Genomics; Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study; Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015. PMID: 30343943; PMCID: PMC6216110.
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Monday, April 6, 2026
Cardiac disease burden in DDX3X syndrome
Carlos Gallego-Navarro, Jeanne L. Theis, Radhika Dhamija et al. Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes, 01 April 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-9059706/v1]
Abstract
Background
DDX3X-syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X-syndrome.
Methods
We conducted a retrospective chart review of patients diagnosed with DDX3X-syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X-syndrome.
Results
A total of 200 patients with DDX3X-syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X-syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects.
Conclusion
DDX3X-syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.
Abstract
Background
DDX3X-syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X-syndrome.
Methods
We conducted a retrospective chart review of patients diagnosed with DDX3X-syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X-syndrome.
Results
A total of 200 patients with DDX3X-syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X-syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects.
Conclusion
DDX3X-syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.
Thursday, March 26, 2026
More on ARHGEF9 mutations
Wang JY, Zhou P, Wang J, Tang B, Su T, Liu XR, Li BM, Meng H, Shi YW, Yi YH, He N, Liao WP. ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation. Neurogenetics. 2018 Jan;19(1):9-16. doi: 10.1007/s10048-017-0528-2. Epub 2017 Nov 13. PMID: 29130122.
Abstract
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.
Ghesh L, Besnard T, Nizon M, Trochu E, Landeau-Trottier G, Breheret F, Thauvin-Robinet C, Bruel AL, Kuentz P, Coubes C, Cuisset L, Mignot C, Keren B, Bézieau S, Cogné B. Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder. Hum Mutat. 2021 May;42(5):498-505. doi: 10.1002/humu.24188. Epub 2021 Mar 14. PMID: 33600053.
Abstract
ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occurring de novo, may be responsible for an X-linked dominant disorder affecting males and females.
Aarabi M, Kessler E, Madan-Khetarpal S, Surti U, Bellissimo D, Rajkovic A, Yatsenko SA. Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation. Eur J Med Genet. 2019 Apr;62(4):239-242. doi: 10.1016/j.ejmg.2018.07.021. Epub 2018 Jul 23. PMID: 30048823.
Abstract
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24 kb and 56 kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.
See: https://childnervoussystem.blogspot.com/2026/03/arhgef9-mutations.html
Abstract
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.
Ghesh L, Besnard T, Nizon M, Trochu E, Landeau-Trottier G, Breheret F, Thauvin-Robinet C, Bruel AL, Kuentz P, Coubes C, Cuisset L, Mignot C, Keren B, Bézieau S, Cogné B. Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder. Hum Mutat. 2021 May;42(5):498-505. doi: 10.1002/humu.24188. Epub 2021 Mar 14. PMID: 33600053.
Abstract
ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occurring de novo, may be responsible for an X-linked dominant disorder affecting males and females.
Aarabi M, Kessler E, Madan-Khetarpal S, Surti U, Bellissimo D, Rajkovic A, Yatsenko SA. Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation. Eur J Med Genet. 2019 Apr;62(4):239-242. doi: 10.1016/j.ejmg.2018.07.021. Epub 2018 Jul 23. PMID: 30048823.
Abstract
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24 kb and 56 kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.
See: https://childnervoussystem.blogspot.com/2026/03/arhgef9-mutations.html
Wednesday, March 25, 2026
KDM2B-related neurodevelopmental disorder
Inspired by a patient
Abstract
The KDM2B-related neurodevelopmental disorder is a recently identified Mendelian disorder of the epigenetic machinery associated with pathogenic variants in KDM2B. Global developmental delay, intellectual disability, congenital anomalies, and systemic manifestations characterize the disorder. Variants in KDM2B that primarily affect the CxxC DNA-binding domain are strongly linked to a specific epigenetic signature. We present three children with KDM2B-related neurodevelopmental disorder, each with a heterozygous variant in the CxxC domain of KDM2B. Patient 1 is a 2-year-old boy with developmental delay, solitary kidney, atrial septal defect, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 2 is a 2-year-old girl with global developmental delay, hip dysplasia, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 3 is a 5-year-old girl with autism, developmental delay, atrial septal defect, and ventricular septal defect, hypertrichosis, atopic dermatitis, and myopic astigmatism. Genetic analysis revealed a variant in KDM2B in each patient. Targeted methylation analysis for the epigenetic signature associated with the KDM2B-related syndrome revealed an abnormal methylation pattern consistent with a positive epigenetic signature of the disorder in individuals 2 and 3. These results provided supportive functional evidence for KDM2B-related neurodevelopmental disorder in the context of the clinical findings and KDM2B variants. Our findings emphasize the value of integrating genomic and epigenomic analyses for variant interpretation. This case series reinforces the consistent phenotype of KDM2B-related neurodevelopmental disorder and highlights ocular and dermatologic manifestations as recurring features in affected individuals.
van Jaarsveld RH, Reilly J, Cornips MC, Hadders MA, Agolini E, Ahimaz P, Anyane-Yeboa K, Bellanger SA, van Binsbergen E, van den Boogaard MJ, Brischoux-Boucher E, Caylor RC, Ciolfi A, van Essen TAJ, Fontana P, Hopman S, Iascone M, Javier MM, Kamsteeg EJ, Kerkhof J, Kido J, Kim HG, Kleefstra T, Lonardo F, Lai A, Lev D, Levy MA, Lewis MES, Lichty A, Mannens MMAM, Matsumoto N, Maya I, McConkey H, Megarbane A, Michaud V, Miele E, Niceta M, Novelli A, Onesimo R, Pfundt R, Popp B, Prijoles E, Relator R, Redon S, Rots D, Rouault K, Saida K, Schieving J, Tartaglia M, Tenconi R, Uguen K, Verbeek N, Walsh CA, Yosovich K, Yuskaitis CJ, Zampino G, Sadikovic B, Alders M, Oegema R. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature. Genet Med. 2023 Jan;25(1):49-62. doi: 10.1016/j.gim.2022.09.006. Epub 2022 Nov 1. PMID: 36322151; PMCID: PMC9825659.
Abstract
Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.
Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature.
Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism.
Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
van Oirsouw ASE, Hadders MA, Koetsier M, Peters EDJ, Assia Batzir N, Barakat TS, Baralle D, Beil A, Bonnet-Dupeyron MN, Boone PM, Bouman A, Carere DA, Cogne B, Dunnington L, Farach LS, Genetti CA, Isidor B, Januel L, Joshi A, Lahiri N, Lee KN, Maya I, McEntagart M, Northrup H, Pujalte M, Richardson K, Walker S, Koeleman BPC, Alders M, van Jaarsveld RH, Oegema R. KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome. Hum Mol Genet. 2025 Aug 16;34(16):1353-1367. doi: 10.1093/hmg/ddaf082. PMID: 40420380; PMCID: PMC12361114.
Abstract
Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.
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