Kwangmi Ahn’s research while affiliated with National Institute of Mental Health, National Institutes of Health and other places

Intellectual disability, in its more common mild form and its more severe form, is the consequence of highly interactive genetic and environmental causes. It is an important area for psychiatrists, as comorbidity with psychiatric disorders is frequent. This chapter presents the causes and clinical features of the best characterized syndromes associated with intellectual disability. Common environmental causes, such as fetal alcohol or lead exposure, and common genetic causes, such as trisomy 21 (Down’s syndrome), are briefly summarized. Classic syndromes, such as tuberous sclerosis, are also presented, though new research identifying many syndromes makes some of these classifications less useful. Prenatal and newborn screenings are fast-developing areas.

Background Chromosomal Copy Number Variants (CNVs) associated with schizophrenia also carry etiological risk for neurodevelopmental disorders, including autism and intellectual deficiency. It is not known however what is their risk for any disorders. Here we applied well-replicated ‘neurodevelopmental’ CNVs (NRXN1 del, MYT1L dup, 15q13.3 del/dup, 16p11.2 del/dup, and 22q11.2 del/dup) and interrogated their frequency and overall clinical penetrance for broad categories of disorder in a general pediatric population. Methods Eight selected CNVs were screened utilizing TaqMan within a population sample of 60,644 pediatric patients. CNV carriers were examined with respect to pre-scored digitized pediatric records and compared to records for a 5:1 non-carrier control group matched for each individual CNV. Prevalence for 12 clinical categories were estimated. Results Seven of these CNVs (NRXN1 (del), MYT1L (dup), 22q11 (dup), 16p11 (dele/dup), and 15q11.3 (del/dup)) were detected in the pediatric population at expected rates based on large control population studies. Having any CNV predicted an increase for two of the 12 disease categories after Bonferroni correction: Nervous system (p=1.43×10-5) and mental/neurodevelopmental disorder (p=2.9×10-10), and were associated with greater cost of medical care. Individual CNVs were examined in relation to their matched non-carriers for previously described associated disorders. As anticipated, 15q13.3 deletion was associated with mental/neurodevelopmental disorders, and 16p11 deletion was associated with congenital deficits, CNS disorders and mental/neurodevelopmental disorders. 16p11 deletion carriers showed more circulatory disorders than their matched non-carriers. Finally, in addition to association with mental and congenital defects, a significant association was found between 22q11 duplication and pediatric gastrointestinal reflux (p=0.0037) which was more likely to be present in the presence of developmental delay (interaction p=0.0362). Discussion These findings extend previous clinically based studies providing a high prediction of risk for 16p11.2 deletion, 15q13.3 deletion and 22q11.2 duplications. A broader concept of overall clinical penetrance is important for understanding the pathophysiology of these disorders and may inform genetic counseling. To our knowledge, this is the first report of a CNV association (22q11 duplication) for pediatric GERD, which may represent a delay in vagal nerve maturation, and first report of a 16p11 deletion associated with circulatory disorders.

Adult attention-deficit/hyperactivity disorder (ADHD) was a rare diagnosis 30 years ago, but epidemiological studies in the 2000s estimated a prevalence between 2% and 5%.¹ More recent reports suggest there may be a rapid increase in new diagnoses, much as has been found for childhood ADHD.² Changes to diagnostic criteria in DSM-5 (compared with DSM-IV) are likely to lead to further increases. These include lowering the number of symptoms for diagnosis in adults from 6 to 5 and raising the age at onset of childhood symptoms from 7 years to 12 years. Additionally, there has been a switch from an emphasis on clinically significant impairment in DSM-IV to the more lenient requirement that symptoms “interfere” or “lower quality” of day-to-day functioning.

We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (α7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.

Objective: Childhood-onset schizophrenia (COS) is a rare but severe form of the disorder, which is often treatment refractory. Short-term studies have indicated a greater differential efficacy, evident through effect sizes, favoring clozapine over other agents in alleviating negative symptoms in COS patients compared with adult-onset patients (AOS). There have been no data for COS patients on long-term compliance with clozapine treatment. Therefore, we wanted to know, over a span of up to 24 years, how many of our COS cohort had remained on clozapine for at least 2 years. We review short-term treatment data and present updated long-term data on compliance and functioning for our patients. Methods: We present the results for long-term medication maintenance over a 24 year observation period for our cohort of 131 patients. Of this cohort, 91.6% (120) were available for follow-up information from either in-person or telephone contact with the patient and/or family members. We defined clozapine compliance as ≥2 years receiving this medication and doing well. Results: We were able to contact 120 of the 131 patients. In spite of the additional cost and inconvenience of regular blood monitoring, 87 patients (72.5%, 87/120) adhered to long-term clozapine maintenance therapy with dosages ranging from 50 to 900 mg, and a median dosage of 500 mg. This rate exceeds the long-term clozapine maintenance rates reported for AOS patients. Conclusions: Short-term data on differential efficacy and long-term maintenance data suggest a possibly greater efficacy of clozapine, relative to other antipsychotics, in COS than in AOS. Our overall findings indicate that very early-onset schizophrenic patients may be more responsive to clozapine. This extends other support for clozapine as an option in the treatment of early-onset schizophrenia.

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.European Journal of Human Genetics advance online publication, 28 October 2015; doi:10.1038/ejhg.2015.218.