UNC13A-related neurodevelopmental disorders in children

Zhao HQ, Li XZ, Ma Y, Wang R, Zhang JZ, Hui L, Liu H, Zou LP, Wang Y. UNC13A-related neurodevelopmental disorders in children: epilepsy phenotypes and antiseizure medication response. Seizure. 2026 Aug;140:204-211. doi: 10.1016/j.seizure.2026.06.003. Epub 2026 Jun 17. PMID: 42385283.

Abstract

Purpose: Pathogenic UNC13A variants are increasingly recognized in pediatric neurodevelopmental disorders, but epilepsy phenotypes and antiseizure medication (ASM) responses remain poorly characterized. This study aimed to define the epileptic spectrum of UNC13A-related disorders in children and identify effective ASM strategies.

Methods: We retrospectively analyzed 10 children with pathogenic/likely pathogenic UNC13A variants. Clinical data, seizure phenotypes, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and ASM outcomes were systematically evaluated.

Results: We identified 10 patients, including eight with de novo heterozygous variants and two with biallelic variants. Most missense variants were localized within the critical hinge regions of Munc13-1, with p.Pro814Leu identified as a recurrent variant in three individuals. Six patients (60%) presented with developmental and epileptic encephalopathy, with a median seizure onset of 19 months (range: 5 months-7 years). Focal seizures were the predominant seizure type, and all affected patients experienced status epilepticus. Febrile seizures occurred in half of these patients. While seizures were largely refractory, levetiracetam (LEV) was observed effective in three out of four treated patients. Genotype-phenotype analysis revealed distinct clinical trajectories: biallelic variants resulted in catastrophic early-onset symptoms and early mortality, whereas heterozygous variants were characterized by drug-resistant epilepsy, tremor and ataxia.

Conclusions: UNC13A variants represent an underrecognized cause of developmental and epileptic encephalopathy in children, characterized by refractory seizures, a high incidence of status epilepticus, and increased susceptibility to febrile seizures. Preliminary observations noted favorable clinical outcomes in a small subset of patients treated with LEV.

Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691-2704. doi: 10.1038/s41588-025-02361-5. Epub 2025 Oct 22. PMID: 41125872; PMCID: PMC12597829.

Abstract

The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.

Ohno K, Ito M, Ohkawara B. Review of 40 genes causing congenital myasthenic syndromes. J Hum Genet. 2025 Jun 18. doi: 10.1038/s10038-025-01355-9. Epub ahead of print. PMID: 40533459.

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50).

See: https://childnervoussystem.blogspot.com/2024/05/unc13a-mutation-and-congenital.html

https://childnervoussystem.blogspot.com/2023/12/unc13a-mutation-as-cause-of-congenital.html

The false compassion of assisted suicide.

Pope Leo XIV called for an end to medically assisted suicide during a visit to medical facilities in Lourdes, France, on Sunday.

The pope gave Mass in Lourdes before addressing a large crowd who cheered as he emphatically affirmed the dignity of all human lives and admonished listeners to reject the "false compassion" of assisted suicide.

"It is precisely in the name of this inalienable dignity of the human person that we must reject the temptation to cause death under the guise of false compassion," the pope said, speaking in French.

"It is impossible to regard causing death as something normal. What is legal is not necessarily moral," he continued. "Here in Lourdes, the city of the sick and of hope, I appeal to the entire healthcare community to remember the profound meaning of your vocation, which is to care for a suffering person, not to eliminate that person."

"No one ever has the right based on laboratory algorithms to decide the life of a given embryo or elderly person. Medicine must never become the servant of programmed death," he said.

Assisted suicide is legal in many Western countries, including France.

The practice has come under heavy criticism, particularly in Canada where it has seen widespread use.

Last week, the family of an 83-year-old Canadian woman demanded answers after she died through the country's medical assistance in dying program despite allegedly becoming distraught when told the procedure would end her life.

Her granddaughter, Brigitte Kranendonk, said that she was her grandmother’s primary caregiver and that her family had decided to place Stegemann at The Pearl care home in Cannifton due to physical and mental decline.

But according to Kranendonk, her grandmother still had a good appetite even following a stomach cancer diagnosis, and rejected the idea of using MAID when it was presented as an option.

Kranendonk said she was present for Stegemann's second MAID assessment, and said that the doctor used "really loose terms, never using the words death or dying."

"She explains MAID to my grandmother by saying: 'We’re going to give you medicine, you’re going to feel at peace. And I just want you to know that you won’t have a bowel movement,'" Kranendonk said.

When Kranendonk interjected and said, "She doesn’t understand what you’re saying," the doctor allegedly looked at Stegemann and said, "We’re going to make sure you won’t have any more pain."

According to a doctor, Stegemann was "deemed fit for MAID, and we're going to proceed," The Daily Mail reported.

Kranendonk said that two days before Stegemann's death, she asked her grandmother directly whether she understood that the scheduled procedure meant she would die.

According to Kranendonk's account to the outlet, Stegemann began crying and said she had "made a mistake."

Stegemann was allegedly told by the doctor her grandmother could "deny" MAID on the day of the procedure, but Stegemann was already unsure if her grandmother had actually consented to it, did not want to cause her more stress, and wanted to enjoy what could be the last few days she had left with her grandmother.

Anders Hagstrom

https://www.foxnews.com/world/pope-leo-calls-false-compassion-medically-assisted-suicide-french-hospital-visit

See: https://childnervoussystem.blogspot.com/2026/09/protection-compassion-and-carenot-death.html

Peddling medically assisted death

A Canadian man battling a debilitating neurological disease told Fox News Digital that hospital staff repeatedly raised the possibility of medically assisted death while he was fighting for the home care he says he needs to survive.

Roger Foley, who has spinocerebellar ataxia, told Fox News Digital in a recent interview that the conversations began in 2016 at Victoria Hospital, part of the London Health Sciences Centre in Ontario, where he says he has remained hospitalized for years while seeking a self-directed home-care arrangement.

In a July 7, 2026, letter obtained by Fox News Digital, Foley's attending physician said he could safely leave the hospital if the Ontario government authorized an individualized home-care arrangement.

"By any reasonable clinical standard, you could be discharged from our hospital if you had adequate support at home," wrote Dr. George K. Dresser, an attending internal medicine physician at London Health Sciences Centre.

Dresser said Foley has been medically stable for much of his prolonged hospitalization, despite suffering hospital-acquired infections, and argued that conventional home-care programs have failed to accommodate his complex medical needs.

"You have been at London Health Sciences Centre because the unique needs that you have cannot be met by existing programs in the community," the physician wrote.

Dresser described Foley as "a square peg in a round hole," arguing that the hospital's standardized approach to care is poorly suited to a patient who requires consistent caregivers and highly individualized assistance.

The physician also suggested that keeping Foley hospitalized may be unnecessarily expensive for Ontario's healthcare system.

"A community-based, self-directed arrangement would in all likelihood cost substantially less than continued acute admission, while delivering far better-matched care," Dresser wrote.

He urged Ontario's Ministry of Health to authorize funding that would allow Foley to recruit, train and manage his own personal support workers, potentially ending his yearslong hospitalization.

Foley alleged that assisted dying was raised again during a disputed discharge process in 2017, when he says he was threatened with daily hospital charges of approximately $1,500 if he did not accept the care arrangements being offered.

"I don't want to die," Foley told Fox News Digital, describing his determination to return to his apartment with caregivers of his choosing.

Foley also alleged that the hospital removed lighting accommodations for his neurological condition in May 2025, making it difficult for him to receive care and consume food and fluids.

Foley said the lighting dispute is particularly serious because his neurological condition makes him sensitive to certain wavelengths of light, including those emitted by fluorescent fixtures.

For years, he said, the hospital accommodated his condition with amber-spectrum lighting that allowed caregivers to assist him without triggering his symptoms.

But in May 2025, Foley alleged the hospital withdrew those accommodations and began requiring staff to provide care under fluorescent lighting.

He claimed the change has made it increasingly difficult to receive routine assistance, including help with eating and drinking, because he must wear large, heavy protective goggles that place additional strain on his already compromised neck.

Foley said he has sometimes relied on personal support workers from outside the hospital to help him consume fluids and that financial limitations have prevented him from arranging enough outside assistance to meet all his needs.

He further alleged that some hospital employees have been instructed not to provide care unless fluorescent lights are turned on, even though he says other staff members have been able to assist him using the amber lighting without difficulty.

Foley also claimed hospital personnel began asking him questions about suicidal thoughts again around the time his lighting accommodations were withdrawn. Unlike his earlier experiences, he said he refused to engage in those conversations because he no longer trusted the hospital's intentions.

He said he does not refuse to discuss his mental health in general, and is not opposed to mental health assessments or receiving appropriate mental health support. However, he said previous experiences with hospital staff have made him wary of engaging in such discussions, especially because he said medical assistance in dying (MAID) had previously been raised as an option.

The allegations mark the latest chapter in what Foley described as a nearly decade-long struggle to obtain the kind of care that would allow him to leave the hospital and return to his own home.

Despite his prolonged hospitalization, Foley said he has never given up his apartment, which he described as accessible and equipped with a ceiling lift to assist with his mobility needs.

"I have my own apartment. I still pay all my bills," he told Fox News Digital.

"The last 10 years I haven't given up my apartment and I have wonderful community [personal support workers] that are ready to start working for me as soon as I get the self-directed funding," Foley said.

Self-directed funding primarily refers to the Direct Funding (DF) Program for adults with physical disabilities and Family-Managed Home Care for broader home care services.

Under such a model, Foley explained, patients with disabilities would have greater control over choosing and managing their caregivers rather than relying exclusively on agencies selected through the provincial home-care system.

Foley argued that this would provide more consistent and safer care, particularly for patients with complex medical needs who require caregivers familiar with their individual conditions.

He said his physicians have supported his efforts to obtain alternative home-care arrangements, but he has been unable to secure the funding necessary to put his plan into action.

Foley said that the existing system has left him caught between remaining hospitalized indefinitely and accepting community-care arrangements he believes would place his health at risk.

"I'm not giving up," he said. "I don't want to die, my daughters know I don't want to die, my physicians have always been very explicit and direct that it's not safe to put me in that type of close model that I need direct funding."

In the letter from Dresser, Foley's attending physician, he writes in part, "I am therefore advocating that the Ministry to consider authorizing an individualized, self-directed funding arrangement that would enable you to be discharged from acute care and to arrange and direct your own care in the community. I am very willing to meet with Ministry staff, to provide whatever clinical documentation is required, and to work collaboratively on the design and safeguards of such an arrangement."

Before his illness progressed, Foley said he had built a career in banking, worked as a television host and comedian, and even trained as a professional wrestler.

He described earning recognition for his work before his deteriorating health eventually forced him to leave his career and go on long-term disability.

But Foley said he has continued looking for ways to contribute to society despite his physical limitations.

He is now involved with a project called "Bring Roger Home," which he said is working with a nonprofit organization to raise money for the care he needs to return to his community.

The effort also includes releasing music he recorded years earlier, with proceeds intended to support his home-care needs and eventually help other people facing similar circumstances.

One of the songs, "Limitless with Limitations," reflects the philosophy he said helped him come to terms with his condition.

"Just because you're not the person that you were doesn't mean that the person you are can't be limitless and achieve positive things and goals," Foley said.

He also urged people living with disabilities or chronic illnesses not to lose hope, even when their medical circumstances become overwhelming.

"Don't give up who you are at your core and believe in yourself," he said.

Foley said his ultimate goal remains unchanged: to return home, reconnect with family and friends, and live as independently as his condition allows.

His experience has also shaped his opposition to Canada's Medical Assistance in Dying (MAID) system, which he argues cannot be adequately safeguarded when patients face serious gaps in medical care and social support.

According to the BBC, Canada’s MAID law, which legalized euthanasia in 2016, is responsible for one in every 20 deaths in Canada.

Foley contended that patients should have meaningful access to treatment, disability assistance and home-care alternatives before assisted death is considered.

For him, the central issue is not whether he has the ability to end his life, but whether he can obtain the assistance necessary to continue living it.

"Even in the darkest times," Foley said, "you can still find a light at the end of the tunnel to go towards."

Fox News Digital reached out to London Health Sciences Centre (LHSC), which operates Victoria Hospital, Ontario Health atHome, the Ontario Ministry of Health, and Dresser, Foley’s physician, for comment but did not immediately receive responses.

Cheshire Independent Living Services declined to comment.

Rachel del Guidice

https://www.foxnews.com/media/disabled-canadian-man-says-hospital-repeatedly-offered-assisted-death-fought-care-stay-alive

Premature burial

A community in Guatemala was shocked when a teenage girl they reportedly thought was dead woke up inside her own coffin.

Fifteen-year-old Yuleidy Ixcotoyac passed out while she was in the car with her father who was driving her to a hospital, news.com.au reported Tuesday.

The teen had reportedly been having chest pains when the incident happened Saturday, and her father, Pastor Abraham Ixcotoyac, checked her pulse and breathing after he stopped their vehicle.

He claimed he could not detect any signs of life, so he believed she was dead and decided not continue the journey to the hospital. Reports said the family never received a confirmed diagnosis or death certificate for the girl and decided to proceed with her funeral which took place eight hours later, according to WION.

Burying someone soon after they die is customary in Guatemala, therefore, her family bought a coffin and placed her inside of it.

However, everyone was shocked when something incredible happened at the family’s home in El Jocote. While looking at her daughter in the casket, the girl’s mother said she saw her move and insisted that she was not dead as everyone believed.

“When I was crying on top of her casket, we opened the window, and she was moving, she was waking up, and suddenly she sat up,” the woman recalled.

Video footage showed the moment the girl was seen sitting up with friends and family around her. One person held a cup to her mouth while others clapped and shouted, “Hallelujah!”

Following the harrowing ordeal and nearly being buried alive, Yuleidy is now recovering at home.

“My heart started hurting really badly, it felt heavy and then I blacked out, like I fainted,” she told reporters.

Social media users shared their thoughts on the reports, one person writing, “And that is why it is called a ‘Wake,'” while someone else said, “There are a few steps missing here before the wake? lol.”

According to the Britannica website, the term “wake” refers to an ancient religious practice:

A wake is a religious rite that traditionally involves mourners staying awake to watch over the body of a deceased person the night before the person’s burial. The term wake has its roots in ancient customs, particularly in the British Isles. The original purpose of a wake was rooted in the belief that evil spirits might harm or even steal the body of the deceased. By staying awake and keeping watch, family and friends could protect the body from such malevolent forces. The Anglo-Saxons referred to this custom as lich-wake, with lich meaning corpse.

The teenager reportedly said she “thanks God” she is alive after the incident.

Amy Furr

https://www.breitbart.com/latin-america/2026/10/13/watch-teenager-wakes-up-inside-her-own-casket-at-funeral-in-guatemala/

ZNF292 mutations 2

Inspired by a patient

Shen Y, Pan R, Liu C, Zheng J, Yang X. De Novo ZNF292 Variants Cause Neurodevelopmental Disorder with Short Stature: A Clinical Case Series of Eight Individuals. Genes (Basel). 2026 Aug 13;17(8):950. doi: 10.3390/genes17080950. PMID: 42650143; PMCID: PMC13512819.

Abstract

Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.

Hao-Fountain Syndrome

Schaaf C, Sailer S. USP7-Related Hao-Fountain Syndrome. 2025 Dec 4. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 41343689.cxcx/

Excerpt

Clinical characteristics: USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.

Diagnosis/testing: The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.

Genetic counseling: USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Korchak EJ, Sharafi M, Jaen Maisonet I, Salazar-Chaparro A, Semenova IV, Khan H, O'Neil AL, Caro P, Schaaf CP, Buhrlage SJ, Bezsonova I. Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2510252122. doi: 10.1073/pnas.2510252122. Epub 2025 Sep 22. PMID: 40982686; PMCID: PMC12501124.

Abstract

Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.

Wimmer MC, Brennenstuhl H, Hirsch S, Dötsch L, Unser S, Caro P, Schaaf CP. Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum. Clin Genet. 2024 May;105(5):499-509. doi: 10.1111/cge.14480. Epub 2024 Jan 14. PMID: 38221796.

Abstract

Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

Rafeienejad F, Keyhani E, Akbarfahimi N, Nouri N. Neurodevelopmental disorder: Hao-Fountain syndrome with USP7 mutation-a case report. J Med Case Rep. 2025 Jul 24;19(1):363. doi: 10.1186/s13256-025-05403-y. PMID: 40707997; PMCID: PMC12291276.

Abstract

Background: Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder manifesting as several known symptoms, including speech and language delay, behavioral abnormalities, and intellectual disability. This rare condition is usually diagnosed by heterozygous deletion or mutation in the ubiquitin-specific protease 7 gene in conjunction with phenotype features.

Case presentation: We report the case of a 5-year-old Persian girl with this rare syndrome. The process of diagnosis, from perinatal examinations to the latest laboratory and clinical tests, is described for the first time in Iran.

Conclusion: Reporting all the symptoms of such a rare genetic case in detail emphasizes the importance of interdisciplinary teamwork and the necessity of raising awareness among therapists about probable upcoming problems; sharing such evident information with parents would help them manage the complexity of raising children with rare syndromes.

TUBGCP6 mutations

Inspired by a patient

Sengillo JD, Ashkenazy N, Shoji MK, Iyer P, Robles-Holmes HK, Lopez A, Yannuzzi NA, Negron CI, Berrocal AM. Familial Exudative Vitreoretinopathy-Like Phenotype in a Patient With Microcephaly and TUBGCP6 Mutations. J Vitreoretin Dis. 2023 Apr 10;7(4):344-347. doi: 10.1177/24741264231167236. PMID: 37927319; PMCID: PMC10621710.

Abstract

Purpose: To describe a case of microcephaly, unilateral retinal fold, and familial exudative vitreoretinopathy (FEVR)-like phenotype in the context of 2 TUBGCP6 variants. Methods: A case and its findings were analyzed. Results: A 4-month-old boy with no family history of eye disease presented by referral for management of presumed persistent fetal vasculature in the left eye. An external examination showed microcephaly. The patient grimaced to light in both eyes, and the anterior segments were unremarkable. On dilated fundus examination, diffuse chorioretinal atrophy was present bilaterally. In the left eye, a retinal fold emanated from the optic nerve head. There was early termination of retinal vasculature, especially in zone 3 in the left eye, resembling a FEVR-like phenotype. Panel-based genetic testing was performed and found 2 mutations in TUBGCP6. Conclusions: Microcephaly, chorioretinopathy, and retinal folds may be associated with TUBGCP6 mutations and masquerade as PFV.

Shurygina MF, Simonett JM, Parker MA, Mitchell A, Grigorian F, Lifton J, Nagiel A, Shpak AA, Dadali EL, Mishina IA, Weleber RG, Yang P, Pennesi ME. Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):2. doi: 10.1167/iovs.61.13.2. PMID: 33137195; PMCID: PMC7645200.

Abstract

Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6.

Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression.

Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients.

Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.

Hull S, Arno G, Ostergaard P, Pontikos N, Robson AG, Webster AR, Hogg CR, Wright GA, Henderson RHH, Martin CA, Jackson AP, Mansour S, Moore AT, Michaelides M. Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. Am J Ophthalmol. 2019 Nov;207:87-98. doi: 10.1016/j.ajo.2019.05.001. Epub 2019 May 8. PMID: 31077665.

Abstract

Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.

Design: Retrospective case series.

Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

Results: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.

Conclusions: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.