De novo variant of SETD1A causes neurodevelopmental disorder with dysmorphic facies: A case report

A 7-year-old female was born after a full-term pregnancy. Enlarged ventricles (0.7–1.0 cm) were observed during pregnancy without hydrocephalus. Large head circumference (39 cm), hypotonia, facial hemangioma, patent foramen ovale, and hypothyroidism were found after birth. The Bayley Scales of Infant and Toddler Development, Second Edition (BSID-II), at about 11 months of age revealed a motor development index <50, the development level equivalent to a 6-month-old infant. The cognitive development index was 64, equivalent to a 7-month-old infant. Head magnetic resonance imaging (MRI) suggested bilateral white matter dysplasia and ventriculomegaly (Supplement Fig. S1A– D). Chromosome karyotype analysis, copy number variations, and screening of congenital metabolic disorders showed no abnormalities. When the child was 3 years old, generalized tonic-clonic seizures occurred. Video electroencephalogram (VEEG) revealed mild background slowing (Supplement Fig. S1F, G). Her seizures were effectively controlled by levetiracetam, and there were no seizures for 4 years. Two days before admission, her epilepsy reemerged. An emergency blood glucose test revealed a blood glucose level of 1.3 mmol/L but returned to normal levels after receiving glucose supplementation. Physical examination showed a height of 114 cm (1 SD–2 SD), a weight of 21.5 kg (P25), and a head circumference of 58.5 cm (>3 SD). She displayed specific abnormal facial features of macrocephaly, high forehead, low nose bridge, inverted nostril, thick lips, and a thin face. Additionally, her facial and physical features act asymmetrically, left limbs were smaller on the left than the right side, head deviation to the left, torticollis, right-eye strabismus, short and thick fingers, flat feet, soft soles, and deformed feet (obvious on right foot: middle toe bent inward, right fourth toe short, parallel to the fifth toe) (Supplement Fig. S2A). The sternum is slightly valgus with mild hypotonia and hypertrichosis. Interictal arterial spin labeling MRI (Supplement Fig. S1E) displayed relative hyperperfusion in multiple areas of the left brain and left cerebellar. Repeated VEEG showed no obvious abnormality. A de novo variant in SETD1A (SET domain-containing protein 1A) was detected [NM_014712.3: exon8: c.2120_2121insA (p.Gly708Argfs*117)] caused by an insertion between 708th and 709th amino acid resulting in a truncated protein via early termination. Sanger sequencing confirmed the variant in her family (Supplement Fig. S2B). The variant was not detected in public databases and classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines (Supplement Table S1). Other pathogenic variants of genes known to be associated with development, epilepsy, or intellectual disability were not found in the proband. According to the clinical manifestations, SETD1A gene mutation, and previous literature reports, the girl was diagnosed with SETD1A-related neurodevelopmental disorder with dysmorphic facies. She started rehabilitation training at 1 year old, and her language development was fair. The patient was followed up with for 6 months. Slightly uncoordinated movement and posture as well as poor balance were observed. However, her cognitive level continued to improve (Wechsler Intelligence Scale for Children [WISC] score of 65). Currently, she is enrolled in kindergarten and her verbal memory is good. She can communicate normally with slightly slower reaction times and poor logical thinking. Recently, there was a short attention span and poor control of urine and feces, but no feeding difficulties. SETD1A is a member of the COMPASS (complex proteins associated with Set1) family of proteins, all of which have H3K4 methyltransferase activity and are closely related to neural development. SETD1A has been identified as a risk gene for schizophrenia, and individuals with SETD1A variants may

A 7-year-old female was born after a full-term pregnancy. Enlarged ventricles (0.7-1.0 cm) were observed during pregnancy without hydrocephalus. Large head circumference (39 cm), hypotonia, facial hemangioma, patent foramen ovale, and hypothyroidism were found after birth. The Bayley Scales of Infant and Toddler Development, Second Edition (BSID-II), at about 11 months of age revealed a motor development index <50, the development level equivalent to a 6-month-old infant. The cognitive development index was 64, equivalent to a 7-month-old infant. Head magnetic resonance imaging (MRI) suggested bilateral white matter dysplasia and ventriculomegaly (Supplement Fig. S1A-D). Chromosome karyotype analysis, copy number variations, and screening of congenital metabolic disorders showed no abnormalities. When the child was 3 years old, generalized tonic-clonic seizures occurred. Video electroencephalogram (VEEG) revealed mild background slowing (Supplement Fig. S1F, G). Her seizures were effectively controlled by levetiracetam, and there were no seizures for 4 years. Two days before admission, her epilepsy reemerged. An emergency blood glucose test revealed a blood glucose level of 1.3 mmol/L but returned to normal levels after receiving glucose supplementation. Physical examination showed a height of 114 cm (1 SD-2 SD), a weight of 21.5 kg (P25), and a head circumference of 58.5 cm (>3 SD). She displayed specific abnormal facial features of macrocephaly, high forehead, low nose bridge, inverted nostril, thick lips, and a thin face. Additionally, her facial and physical features act asymmetrically, left limbs were smaller on the left than the right side, head deviation to the left, torticollis, right-eye strabismus, short and thick fingers, flat feet, soft soles, and deformed feet (obvious on right foot: middle toe bent inward, right fourth toe short, parallel to the fifth toe) (Supplement Fig. S2A). The sternum is slightly valgus with mild hypotonia and hypertrichosis. Interictal arterial spin labeling MRI (Supplement Fig. S1E) displayed relative hyperperfusion in multiple areas of the left brain and left cerebellar. Repeated VEEG showed no obvious abnormality.
A de novo variant in SETD1A (SET domain-containing protein 1A) was detected [NM_014712.3: exon8: c.2120_2121insA (p.Gly708Argfs*117)] caused by an insertion between 708th and 709th amino acid resulting in a truncated protein via early termination. Sanger sequencing confirmed the variant in her family (Supplement Fig. S2B). The variant was not detected in public databases and classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines (Supplement Table S1). Other pathogenic variants of genes known to be associated with development, epilepsy, or intellectual disability were not found in the proband.
According to the clinical manifestations, SETD1A gene mutation, and previous literature reports, the girl was diagnosed with SETD1A-related neurodevelopmental disorder with dysmorphic facies. She started rehabilitation training at 1 year old, and her language development was fair. The patient was followed up with for 6 months. Slightly uncoordinated movement and posture as well as poor balance were observed. However, her cognitive level continued to improve (Wechsler Intelligence Scale for Children [WISC] score of 65). Currently, she is enrolled in kindergarten and her verbal memory is good. She can communicate normally with slightly slower reaction times and poor logical thinking. Recently, there was a short attention span and poor control of urine and feces, but no feeding difficulties.
SETD1A is a member of the COMPASS (complex proteins associated with Set1) family of proteins, all of which have H3K4 methyltransferase activity and are closely related to neural development. SETD1A has been identified as a risk gene for schizophrenia, and individuals with SETD1A variants may  (Table 1). [2][3][4] Compared with previous reports, our case showed novel phenotypes such as macrocephaly, hypertrichosis, stubby fingers, and unique face and toe deformities, namely, the facial features, trunk, and limbs on the left side were relatively smaller than that on the right. In addition, our patient had no obvious speech development disorder or behavioral abnormality. Levetiracetam is effective in the treatment of seizures in our case. In addition, there was another report that showed phenobarbital to improve SETD1A-related epilepsy. 4 This case enriches our understanding of SETD1A-related neurodevelopmental disorders, expanding the phenotype and genotype spectrum. Through literature review, we also found that the truncating variants were more severe in clinical phenotypes, most of which were accompanied by mental and behavioral disorders, facial deformities, and short stature. This case provides valuable information for clinical diagnosis and genetic counseling. Figure S1. Head magnetic resonance imaging suggested bilateral white matter dysplasia and ventriculomegaly (Fig. 1A, 1B, 1C, 1D). Video electroencephalography revealed mild background slowing (Fig. 1F, 1G) Figure S2. The patient's facial and physical features act asymmetrically, left limbs smaller on the left than the right side, head deviation to the left, torticollis, right-eye strabismus, short and thick fingers, flat feet, soft soles, and deformed feet ( Fig. 2A). Pedigree and Sanger sequencing of the family confirmed the variant in her family (Fig. 2B). Neuropsychiatric symptoms are not uncommon in patients with autoimmune diseases, including inflammatory bowel disease (IBD). 1 The link between the two is bidirectional with multiple and additive causes. These include the impact of chronic illness on well-being 2 and the effects of medication used to treat IBD. 3 We report the neuropsychiatric presentation of a 34-year-old man to the emergency department (ED). His medical history included Crohn disease, in remission for 6 years while taking azathioprine, mesalazine, and the biologic adalimumab. Two months before presenting, he switched from reference adalimumab (Humira) to a biosimilar, Imraldi, with his last dose 17 days before presentation.
Two weeks before admission he developed a prodromal illness with lethargy, malaise, and a self-limiting widespread maculopapular rash. He experienced an intense holocranial headache with photosensitivity and vomiting, an unusual taste in his mouth, seeing "multicolored dots on the wall," and excoriation without pruritis. He described low mood, restless sleep, early awakening, and poor concentration. Preoccupied with losing his family, he experienced emotional lability and panic attacks. Transcripts from calls to a crisis line revealed a perplexed, highly anxious state. He attended his local ED and was discharged on promethazine.
That day, he experienced another panic attack and, overwhelmed, took an eight-inch kitchen knife and stabbed himself three times in the abdomen with the intent to die. He expressed regret and denied passivity of control and premeditation, describing derealization, depersonalization, and absence of pain sensation. During his admission, organic causes of psychosis were excluded and he was transferred to a psychiatric facility. He self-discharged the following day with community follow-up and promethazine and zopiclone.