A Novel Mutation in HERC2 Gene in a Patient with Global Developmental Delay, Intellectual Disability, and Refractory Seizures
Intellectual disability is a neurodevelopmental disorder that affects 1 to 3% of the global population. Patients with intellectual disabilities typically lack the skills that are considered necessary for independent daily living. Genetic defects are responsible for the development of intellectual disabilities in approximately 25% of the patients leading to structural and/or functional impairments of the central nervous system. In this article, we report a novel mutation in HERC2 (MIM 605837 and ENSG00000128731) gene in a child who has a global developmental delay, intellectual disability, and refractory seizures.
A 14-year-old girl, a product of a full-term consanguineous pregnancy and normal vaginal delivery, presented to our neurology clinic for a second opinion and further management of seizures. Since birth, her mother noticed a developmental delay when compared with her siblings. The developmental delay was very severe and global including motor functions, language, intelligence, and sphincter control. She also developed refractory seizures of multiple types. She was only relatively controlled using three antiepileptic drugs: levetiracetam 1,500 mg twice daily, valproic acid 400 mg twice daily, and clonazepam 1 mg twice daily. She also had severe psychosocial retardation and attention deficit hyperactivity disorder, and although she was 14 years old, her mental age was that of a 4-year old child. She was also treated with risperidone, 1-mg twice daily and benztropine, 0.5-mg once daily for her psychiatric symptoms. Although her parents were healthy, her family history was remarkable for a first-degree consanguinity with a brother and a sister affected by the same disease.
Examination showed a mentally challenged girl with a stereotypical repetitive hand movement with excessive sialorrhea. She was not able to speak except for moaning sounds. She had a high arched palate and tapered fingers. Her tone was decreased all over but her power was normal. Coordination was difficult to be assessed, and her gait looked normal. Skin, mucous membrane, and systemic examination were normal with no organomegaly. Magnetic resonance imaging of the brain was normal.
The history and clinical examination findings were suggestive of either a genetic or a neurometabolic disorder. The patient was fully investigated including thyroid function test, liver function test, renal function test, metabolic work-up, and neurometabolic screening (e.g., long chain fatty acid). All of the investigations were within normal limits.
Blood samples were collected and sent for genetic testing after obtaining informed written consent according to the Helsinki declaration. The pedigree was drawn after having the detailed family information as shown in [Fig. 1]. The genetic testing detected a previously unreported homozygous variant in the HERC2 gene, c.4043C>T (p.Thr1348lle). This variant was further confirmed with the Sanger sequencing analysis using the primers of the target region. It is located in a highly conserved nucleotide and moderately conserved amino acid position, with moderate physicochemical differences between the exchanged amino acids. The variant is predicted damaging by in silico pathogenicity prediction tools. We calculated the pathogenic score using SIFT 0.88, MutationTaster 1.0, PloyP 1.05, PolyPhen2 0.99, GERP 7.93, SiPhy 17.52 along with CADD (version v1.4) score 19.2. This variant is likely pathogenic as the detailed clinical information of the patient (global developmental delay, intellectual disability, and refractory seizures) is also supporting this report. Furthermore, the patient's phenotypes and family history are highly specific for a disease with a single genetic etiology. Moreover, the prevalence of the p.Thr1348Ile in affected individuals is significantly increased compared with the prevalence in controls. We have shown the conservation of amino acid along with other species in [Fig. 2]. This variant was also detected in a heterozygous state in the proband's parents which confirms homozygosity of the variant in the patient.
The patient continued to be followed up in the outpatient department with a multidisciplinary team including a neurologist, geneticist, physiatrist, social worker, and rehabilitation specialist.
HERC2 gene in humans is located on chromosome 15q11–13, which is called the Prader–Willi/Angelman region. HERC2 gene encodes a protein with ubiquitin ligase activity which has a role in regulating the activity of the tumor suppressor protein p53. In addition, it is a part of several vital cellular processes including DNA repair, iron metabolism, and cell cycle. This indicates that HERC2 has an important role in several physiological and pathological processes. A recent study was conducted to examine the relevance of HERC2 in vivo in a mouse with targeted inactivation of the HERC2 gene. This experiment led to the identification of HERC2 ubiquitin ligase as an essential protein for embryonic development and an important regulator of motor coordination.
Prader–Willi syndrome and Angelman syndrome are caused by a deletion, uniparental disomy, or imprinting defect of the same region of either paternally or maternally inherited human chromosome 15q. In few cases, Angelman syndrome has been associated with pathogenic variants in UBE3A gene, which is also located in chromosome 15q11–13. Loss of HERC2 is frequently observed in patients with Angelman syndrome and seems to contribute to the severity of some features of this disorder including autistic behavior, seizures, and ataxic features. A homozygous mutation in HERC2 gene causes diverse phenotypes in mice known as rjs (runty jerky sterile) and jdf2 (juvenile development and fertility), which mimic symptoms of Prader–Willi syndrome. Pathogenic variants in the HERC2 gene in humans are associated with a severe neurodevelopmental disorder that develops with plagiocephaly, prognathism, strabismus, hypotonia, pronation of the feet, elongated hallux, delayed psychomotor development, intellectual disability, poor language, seizures (in some patients), hypoplasia of the posterior corpus callosum, autistic features, and onset in infancy. Upon reviewing the literature, only three reports have been found, and our case is the fourth report.  
Unfortunately, there is no specific treatment for intellectual disabilities. The only potential intervention supportive is to manage the co-existing symptoms to help the patient achieve the highest possible level of developmental adaptation and function. These supportive interventions include alleviation of gross and fine motor delays, communication strategies such as the use of communication devices and modified sign language, and special education programs. Management of sleep problems is with a combination of pharmacologic therapies and behavioral interventions. Seizures are managed with anticonvulsant medications such as valproic acid, clonazepam, lamotrigine, and levetiracetam. Ketogenic diet and vagal nerve stimulation are considered for patients with seizures refractory to pharmacological medications. Managing disruptive behaviors can be achieved through a behavior modification program, and medications are reserved for aggressive behaviors.
In conclusion, we describe a novel mutation in HERC2 gene c.4043C>T (p.Thr1348lle) in a Saudi patient with an extremely rare neurodevelopmental disorder. In addition, we illustrate the benefits of genetic testing to identify disease-associated mutations in patients with intellectual disabilities in whom a precise clinical diagnosis is lacking. We have a high percentage of consanguinities in Saudi Arabia, and genetic disorders contribute to a major proportion of diseases presenting to the neurology clinic.
Received: 23 February 2020
Accepted: 08 April 2020
16 October 2020 (online)
Georg Thieme Verlag KG
Stuttgart · New York
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