Additional individualized written consent was obtained from the individuals included below who shared more patient-specific information in the following vignettes.

Individual 1 is an 18-year-old male with nonverbal intellectual disability, recurrent gastrointestinal (GI) complaints, and esophagitis, frequent aspiration pneumonia, is non-ambulatory, and has dysmorphic facial features including upturned nares, down-slanting palpebral fissures, and a large mouth. His family history was remarkable for a maternal half-brother with the same phenotype, who died in his early 20 s due to complications from aspiration pneumonia and sepsis. Genetic testing (ASD/ID exome panel) completed during inpatient psychiatric admission identified a maternally inherited variant in ATRX: (NM_000489.6):c.756G > C p.(Glu252Asp). Originally classified as a variant of uncertain significance (VUS) by the reporting lab, functional studies were completed to confirm the diagnosis: a hemoglobin electrophoresis demonstrated decreased hemoglobin A2 consistent with alpha-thalassemia, providing further evidence for the diagnosis. Following diagnosis, the patient had additional GI studies including esophagogastroduodenoscopy and was diagnosed with erosive esophagitis and candidal esophagitis and was prescribed nystatin and lansoprazole. Targeting GI discomfort with medication likely improved overall behavioral symptoms, and the patient to date has not required further inpatient psychiatric management since the time of confirmed genetic diagnosis.

Individual 5 is an 11-year-old female with autism spectrum disorder, intellectual disability, intermittent explosive disorder requiring antipsychotic medications to manage symptoms, and an acute course of neurological decline including slowness, weakness, drooling with trouble eating, and unsteady gait. She has mild dysmorphic facial features including a round face with a prominent forehead, sparse eyebrows, and a bulbous nasal tip. She has an obese habitus. Genetic testing (ASD/ID exome panel) completed during inpatient psychiatric admission identified a variant in SLC6A3: (NM_001044.5):c.1067C > T p.(Thr356Met) which was classified as a VUS. However, upon literature review, this variant had been previously reported in a patient with autism, with functional studies demonstrating persistent dopamine efflux in the dopamine transporter (Ng et al., 2023). Thus, she was given a presumed diagnosis of Dopamine Transporter Deficiency. We hypothesized that this patient’s neurological decline and extrapyramidal exam findings were likely due to excessive dopamine blockade due to a genetic predisposition to reduced dopamine transporter function complicated by antipsychotic medication further decreasing dopamine stores. With this genetic finding, her medications were quickly transitioned away from a first-generation antipsychotic (haloperidol) to an atypical antipsychotic medication targeting mainly serotonin pathways (clozapine). Following this change in medication, her extrapyramidal symptoms resolved. She continues to have behavioral challenges but has not had any recurrence of neurological extrapyramidal symptoms on her current psychiatric medication regimen.

Individual 7 is a 16-year-old female with nonverbal intellectual disability, intermittent explosive disorder, and constipation. The physical exam was notable for bitemporal narrowing, mild hypertelorism, short philtrum, large lips, and widely spaced central incisors. A historical karyotype had been completed when she was a young child and identified a 9q34 deletion of uncertain significance. Genetic testing (chromosomal microarray) was initiated during inpatient psychiatry admission to further clarify the breakpoints of the deletion, and resulted in a microdeletion at 9q34, arr[GRCh37] 9q34.3(139910563_141066491) × 1, which included deletion of the entire EHMT1 gene, diagnostic for Kleefstra syndrome. Following this diagnosis, she underwent a comprehensive GI evaluation due to the many known GI complications found in Kleefstra syndrome (Kleefstra & Leeuw, 1993), and she was discovered to have toxic megacolon. After treatment and escalation of chronic constipation management, her behavioral symptoms improved. Untreated GI discomfort is likely a contributor to behavioral symptoms.

Individual 10 is a 17-year-old male with autism, intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Additional medical history includes large habitus and obesity, non-alcoholic fatty liver disease, high-arched palate, dental crowding, foot pain, and back pain. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry admission identified a likely pathogenic de novo variant in SATB2(NM_001172509.2):c.169G > A p.(Gly57Ser), diagnostic for SATB2-Neurodevelopmental disorder (glass syndrome). Intellectual disability, behavioral challenges, and craniofacial dysmorphology are well described in this condition (Zarate et al., 2024). Furthermore, osteopenia and epilepsy have been reported in patients with this condition. After observing slightly elevated alkaline phosphatase levels on previously completed routine labs, 192 u/L (40–150 u/L normal range) bone density scans were ordered and were normal. With ongoing foot and back pain, x-rays and MRI studies were ordered and demonstrated a hairline toe fracture. The patient was placed in a walking boot to allow for recovery of the fracture. Being vigilant for fracture evaluation in a condition with known osteopenia was important to care for this patient. Bone pain is a likely contributor to behavior outbursts.

Individual 11 is an 11-year-old male with autism, ADHD, anxiety, epilepsy, obstructive sleep apnea, and a repaired laryngeal cleft as an infant. His exam was positive for mild hypertelorism, upturned nares, and downturned corners of the mouth. Genetic testing (exome) completed during inpatient psychiatry admission identified a paternally inherited VUS in POGZ: (NM_015100.4):c.2176C > A p.(Pro726Thr). This variant was later upgraded to pathogenic after diagnostic epigenetic signature testing was completed (Haghshenas et al., 2024). The individual’s father notably had a repaired laryngeal cleft and learning disabilities. This result thus became diagnostic for the father as well. The individual’s father was later able to return to psychiatric care as an adult, and garnered a diagnosis of autism for himself, increased his own mental health therapies, and qualified for additional social security benefits, allowing him more time and financial supports to care for his family as the primary caregiver of this patient and his siblings. Improvements to parental mental health likely have positive outcomes on child behaviors and well-being.

Individual 15 is a 13-year-old male with autism, mild intellectual disability, and intermittent explosive disorder admitted to inpatient psychiatry for aggressive behavior management. Medical history also includes obesity, large stature, and macrocephaly. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry stay identified two variants in TBC1D7. One nonsense variant: TBC1D7 NM_001318809.1:c.6dup p.(Glu3Ter), and an in-trans variant consisting of a duplication of 335 bps in exon 6 arr[GRCh37]chr613,307,82,613,308,161 × 3 predicted to disrupt the reading frame of TBC1D7. Both variants were listed as VUS; however, on review of the literature (Alfaiz et al., 2014), nonsense and loss-of-function biallelic variants have been reported in this gene with a phenotype of patients with intellectual disability and macrocephaly. Thus, with a consistent phenotype and two predicted loss-of-function variants, a clinical diagnosis of TBC1D7-NDD was conferred. As TBC1D7 is the third subunit of the TSC1-TSC2 complex (Dibble et al., 2012), we initiated a trial of rapamycin, an mTOR inhibitor, to target autism comorbidities of aggression and irritability (Mizuguchi et al., 2019). Parental report after 6 months of medication trial was that aggressive symptoms had subjectively improved.

Individual 30 is an individual with autism and intellectual disability, admitted to inpatient psychiatry for self-injurious behavior management. The patient is nonverbal with behavioral stereotypies. Physical exam was notable for up-slanting palpebral fissures and multiple café-au-lait macules on the abdomen, back, and flank, along with axillary freckling. Genetic testing (exome) was initiated during inpatient psychiatry stay and identified a variant in NF1: (NM_001042492.3):c.7870-9 T > G p.? which, though listed as a VUS, was predicted to affect the splice site and alter protein function. As the patient qualified for a clinical diagnosis of NF1 with more than 6 café-au-lait macules and axillary freckling (Legius et al., 2021), the patient was conferred a diagnosis of NF1. Following this diagnosis, an MRI of the brain and orbits was ordered per NF1 tumor surveillance protocols, which identified a plexiform neurofibroma within the supra- and infrazygomatic left masticator space, superficial to the masseter and temporalis muscles, extending into the left temporomandibular joint, with mild anterior displacement of the mandibular condyle. Plexiform neurofibromas can be painful, and in a nonverbal patient it may be difficult to communicate this pain. A high-dose ibuprofen prescription was provided to the patient to treat any presumed pain, which also translated into less frequent behavioral outbursts.

Individual 36 is a 13-year-old male with autism, mild intellectual disability, ADHD, obsessive–compulsive disorder, gastroesophageal reflux disease, and constipation. He is able to communicate in short sentences. On exam, he has macrocephaly and a broad forehead. Genetic testing (exome) was initiated during inpatient psychiatric stay and identified a de novo VUS in CMIP: (NM_198390.3):c.1483G > A p.(Glu495Lys). This variant is located 2 base pairs from a known splice site. With a matching phenotype of autism, GI problems, and large stature, along with a compelling de novo variant, with no other candidate genes identified on broad exome testing, this patient was given a provisional diagnosis of CMIP-NDD. CMIP is a protein expressed in T cells, where its function is inhibition of NF-kB activation (Oniszczuk et al., 2020). Overactive NF-kB can cause inflammation and oxidative stress in the brain, thus we initiated a trial of an antioxidant, resveratrol, to target behavioral symptoms. Parents report improved attention and focus with less irritability after initiation of this medication, and noticeably worsened attention and focus when resveratrol was held during a lapse in medication coverage. Even without a molecularly confirmed pathogenic variant in this case, there is evidence that resveratrol improves symptoms of ADHD and autism (Hendouei et al., 2020), with relatively few side effects. This diagnosis helped us choose a precision medication, and there were positive outcomes and improved behaviors for the individual.

Individual 47 is a 16-year-old female with mild intellectual disability, ADHD, anxiety, OCD, and intermittent explosive disorder. Additional medical history includes ileitis and accompanying recent weight loss. Facial features include a low-hanging columella, bulbous nasal tip, and widely spaced teeth. Genetic testing (ASD/ID exome panel) initiated during inpatient psychiatry admission identified a pathogenic variant in SLC6A8: (NM_005629.3):c.1540C > T p.(Arg514Ter), diagnostic for cerebral creatine deficiency syndrome. She was initiated on creatine, arginine, and glycine supplements, with improvements in attention, focus, and anxiety documented on pre- and post-medication initiation Vanderbilt assessment scales. Parents report that she had improved grades and participation in school, and fewer behavioral outbursts. This patient has been previously reported by our team in a dedicated case report (Tauer et al., 2024).

Individual 54 is an individual with intellectual disability, ADHD, intermittent explosive disorder, microcephaly, a history of failure to thrive as an infant, and bilateral clubfoot status post casting as an infant. Notable facial features include short palpebral fissures, hypotelorism, and upturned nares. Genetic testing (ASD/ID exome panel) sent during inpatient psychiatry admission resulted in a maternally inherited likely pathogenic variant in SMC1A: (NM_006306.4):c.3568A > G p.(Lys1190Glu), diagnostic for X-linked Cornelia de Lange syndrome (CdLS). The patient had not had hearing evaluated since the age of two, so, in following CdLS surveillance guidelines, the patient was referred to audiology for an updated hearing evaluation. The patient was found to have bilateral sensorineural hearing loss and was fitted for hearing aids. N-acetylcysteine was initiated to target symptoms of irritability (Cukrov et al., 2018), with unclear effect to date and follow-up planned to assess further. Uncorrected deficits in hearing can contribute to barriers in communication and cause frustration in educational and other settings Fig. 3.