[Clinical and molecular genetic analysis of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome].

OBJECTIVE: To explore the genetic characteristics of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome (RTT). METHODS: A male infant who was admitted to Gansu Provincial Maternity and Child Health Care Hospital in May 2020 was selected as the study subject. Clinical data of the infant was collected. Genomic DNA was extracted from peripheral blood samples from the infant and his parents, and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 4-day-old male infant, had presented with poor response, poor intake, feeding difficulties, and deceased at 8 months after birth. WES revealed that he has harbored a 0.643 Mb deletion in the 16p11.2 region, which encompassed key genes of the 16p11.2 microdeletion syndrome such as ALDOA, CORO1A, KIFF22, PRRT2 and TBX6. His father has carried the same deletion, but was phenotypically normal. The deletion was predicted to be pathogenic. The child was also found to harbor a maternally derived c.763C>T (p.R255X) hemizygous variant of the MECP2 gene, which was also predicted to be pathogenic (PVS1+PS4+PM2_Supporting). CONCLUSION: The 16p11.2 deletion and the MECP2: c.763C>T (p.R255X) variant probably underlay the pathogenesis in this infant.

Motor difficulties in 16p11.2 copy number variation.

The rare genetic variants 16p11.2 duplication and 16p11.2 deletion have opposing effects on brain structure and function, yet are associated with broadly similar clinical phenotypes that include autism, intellectual impairment, psychiatric illness, and motor difficulties. In recent years, studies have identified subtle distinctions between the phenotypic effects of 16p11.2 duplication and 16p11.2 deletion with respect to patterns of autism, intellectual impairment, and psychiatric illness. However, although divergent phenotypic findings in some motor domains have been reported, no study has yet made a comprehensive comparison of motor difficulties between 16p11.2 deletion and 16p11.2 duplication carriers to elucidate points of convergence and divergence. We sought to make such a comparison in a group of 133 16p11.2 deletion carriers, 122 duplication carriers, and 388 familial controls, hypothesizing that motor impairment would overall be greater in deletion than duplication carriers. In a series of regression models, we found that 16p11.2 deletion status tended to predict greater impairment along indices of gross motor function, but less impairment along indices of fine motor function. These findings point to a potential pattern of performance difficulties that could be investigated in future studies. Elucidating motor differences between 16p11.2 duplication and 16p11.2 deletion carriers may help in understanding the complex effect of 16p11.2 copy number variation and other rare genetic causes of autism.

Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion.

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.2 deletion. However, the specific neuroanatomical mechanisms underlying such alterations, as well as their developmental trajectory, are still poorly understood. Here we explored differences in microstructural brain connectivity between 24 children carrying a 16p11.2 deletion and 66 typically developing (TD) children between 2 and 8 years of age. We found a large pervasive increase of intra-axonal volume widespread over a high number of white matter tracts. Such microstructural alterations in 16p11.2 deletion children were already present at an early age, and led to significant changes in the global efficiency and integration of brain networks mainly associated to language, motricity and socio-emotional behavior, although the widespread pattern made it unlikely to represent direct functional correlates. Our results shed light on the neuroanatomical basis of the previously reported increase of white matter volume, and align well with analogous evidence of altered axonal diameter and synaptic function in 16p11.2 mice models. We provide evidence of a prevalent mechanistic deviation from typical maturation of brain structural connectivity associated with a specific biological risk to develop ASD. Future work is warranted to determine how this deviation contributes to the emergence of symptoms observed in young children diagnosed with ASD and other NDDs.

Clinical implications of additional chromosomal abnormalities in adult acute myeloid leukemia with inv (16)/t(16;16)/CBFB::MYH11.

OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.

Prenatal prevalence and postnatal manifestations of 16p11.2 deletions: A new insights into neurodevelopmental disorders based on clinical investigations combined with multi-omics analysis.

BACKGROUND: The 16p11.2 deletion is one of the most common genetic aetiologies of neurodevelopmental disorders (NDDs). The prenatal phenotype of 16p11.2 deletion and the potential mechanism associated with postnatal clinical manifestations were largely unknow. We revealed the developmental trajectories of 16p11.2 deletion from the prenatal to postnatal periods and to identify key signaling pathways and candidate genes contributing to neurodevelopmental abnormalities. METHODS: In this 5-y retrospective cohort study, women with singleton pregnancies who underwent amniocentesis for chromosomal abnormalities were included. Test of copy-number variations (CNVs) involved single nucleotide polymorphism-array and CNV-seq was performed to detected 16p11.2 deletion. For infants born carrying the 16p11.2 deletion, neurological and intellectual evaluations using the Chinese version of the Gesell Development Scale. For patients observed to have vertebral malformations, Sanger sequencing for T-C-A haplotype of TBX6 was performed. For those infants with clinical manifestations, whole-exome sequencing was consecutively performed in trios to rule out single-gene diseases, and transcriptomics combined with untargeted metabolomics were performed. RESULTS: The prevalence of 16p11.2 deletion was 0.063% (55/86,035) in the prenatal period. Up to 80% (20/25) of the 16p11.2 deletions were proven de novo by parental confirmation. Approximately half of 16p11.2 deletions (28/55) were detected with prenatal abnormal ultrasound findings. Vertebral malformations were identified as the most distinctive structural malformations and were enriched in fetuses with 16p11.2 deletions compared with controls (90.9‰ [5/55] vs. 8.4‰ [72/85,980]; P < 0.001). All 5 fetuses with vertebral malformations were confirmed to have the TBX6 haplotype of T-C-A. Overall, 47.6% (10/21) infants birthed were diagnosed with NDDs of different degrees. Language impairment was the predominant manifestation (7/10; 70.0%), followed by motor delay (5/10; 50%). Multi-omics analysis indicated that MAPK3 was the central hub of the differentially expressed gene (DEG) network. We firstly reported that histidine-associated metabolism may be the core metabolic pathway related to the 16p11.2 deletion. CONCLUSION: We demonstrated the prenatal presentation, incomplete penetrance and variable expressivity of the 16p11.2 deletion. We identified vertebral malformations were the most distinctive prenatal phenotypes, and language impairment was the predominant postnatal manifestation. Most of the 16p11.2 deletion was de novo. Meanwhile, we suggested that MAPK3 and histidine-associated metabolism may contribute to neurodevelopmental abnormalities of 16p11.2 deletion.

A novel case of 16q22.3 duplication syndrome in a child with overgrowth: case report and literature review.

BACKGROUND: Distal chromosome 16 duplication syndrome (also known as 16q partial trisomy) is a very rare genetic disorder recently described in few clinical reports. 16q trisomy is generally associated with a multisystemic phenotype including intrauterine growth restriction (IUGR), brain and cardiac defects, intellectual disability (ID) and an increased risk of both prenatal and postnatal lethality. Smaller copy number variants (CNV) within the 16q region create partial trisomies, which occur less frequently than full trisomy 16q. CASE PRESENTATION: We present the clinical case of a 12-years-old male with a 16q22.3q24.1 de novo heterozygous duplication whose phenotype was characterized by ID, facial dysmorphisms, stature and weight overgrowth. To date, only five other cases of this syndrome have been reported in scientific literature, and none of them comprised overgrowth. CONCLUSIONS: Our case report highlights the great heterogeneity in clinical manifestations and provides new evidence for better defining the phenotypic picture for smaller 16q distal CNVs, suggesting unusual features.

Core-binding factor abnormalities involving chromosome 16 in acute myeloid leukaemia: prognostic and therapeutic implications.

Core-binding factor (CBF) abnormality-associated myeloid neoplasms incorporate acute myeloid leukaemia (AML) (CBF-AML) with translocation t(8;21)(q22;q22.1) (AML1/ETO fusion) and inv(16)(p13.1q22) or translocation t(16;16)(p13.1;q22) (CBFB/MYH11 fusion) abnormalities which confer a favourable prognosis following cytarabine-based induction chemotherapy. Accumulating evidence from the molecular studies have stratified CBF-AML into favourable and unfavourable subgroups based on the associated cooperating mutations that impact the outcome. We describe a case of acute myelomonocytic leukaemia with abnormal eosinophils (M4Eo) in a woman in her 20s who was found to have CBFß/MYH11 fusion along with mutated c-KIT (exon 17) and KRAS (exon 2) genes by next-generation sequencing. She had an aggressive clinical course following initiation of cytarabine-based induction chemotherapy. The underlying mutational landscape may significantly influence the biological behaviour of otherwise favourable risk of CBF-AML cases.

The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples.

BACKGROUND: We present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2-BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index. METHODS: All male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities. RESULTS: On medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with mild attention deficits. The third-born male offspring was only noted as having motor deficits and received a diagnosis of developmental coordination disorder. Other than the 16p11.2 distal deletion, no additional contributing variants of clinical significance were observed. The mother was clinically evaluated and noted as having a broader autism phenotype. CONCLUSION: In this family, the phenotypes observed are most likely caused by the 16p11.2 distal deletion. The lack of other overt pathogenic mutations identified by genomic sequencing reinforces the variable expressivity that should be heeded in a clinical setting. Importantly, distal 16p11.2 deletions can present with a highly variable phenotype even within a single family. Our additional data curation provides further evidence on the variable clinical presentation among those with pathogenetic 16p11.2 (BP2-BP3) mutations.

16p11.2 CNV gene Doc2α functions in neurodevelopment and social behaviors through interaction with Secretagogin.

Copy-number variations (CNVs) of the human 16p11.2 genetic locus are associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, it remains largely unclear how this locus is involved in the disease pathogenesis. Doc2α is localized within this locus. Here, using in vivo and ex vivo electrophysiological and morphological approaches, we show that Doc2α-deficient mice have neuronal morphological abnormalities and defects in neural activity. Moreover, the Doc2α-deficient mice exhibit social and repetitive behavioral deficits. Furthermore, we demonstrate that Doc2α functions in behavioral and neural phenotypes through interaction with Secretagogin (SCGN). Finally, we demonstrate that SCGN functions in social/repetitive behaviors, glutamate release, and neuronal morphology of the mice through its Doc2α-interacting activity. Therefore, Doc2α likely contributes to neurodevelopmental disorders through its interaction with SCGN.

Clinical outcomes of fetuses with chromosome 16 short arm copy number variants.

BACKGROUND: The short arm of chromosome 16 consists of several copy number variants (CNVs) that are crucial in neurodevelopmental disorders; however, incomplete penetrance and diverse phenotypes after birth aggravate the difficulty of prenatal genetic counseling. METHODS: We screened 15,051 pregnant women who underwent prenatal chromosomal microarray analysis between July 2012 and December 2017. Patients with positive array results were divided into four subgroups based on the type of mutation identified on screening (16p13.3, 16p13.11, 16p12.2, and 16p11.2), and the maternal characteristics, prenatal examinations, and postnatal outcomes of different cases were reviewed. RESULTS: Chromosome 16 CNVs were identified in 34 fetuses, including four with 16p13.3 CNVs, 22 with 16p13.11 CNVs, two with 16p12.2 microdeletions, and six with 16p11.2 CNVs. Of the 34 fetuses, 17 delivered without early childhood neurodevelopmental disorders, three developed neurodevelopmental disorders during childhood, and 10 were terminated. CONCLUSION: Incomplete penetrance and variable expressivity make prenatal counseling challenging. Most cases with inherited 16p13.11 microduplication were reported to have normal development in early childhood, and we also report a few cases of de novo 16p CNVs without further neurodevelopmental disorders.

Acute pancreatitis as the initial manifestation of acute myeloid leukemia with chromosome 16 rearrangements.

Acute pancreatitis is an acute inflammatory process of the pancreas that is becoming an increasingly common clinical issue. The most frequent underlying etiologies include gallstones and chronic alcohol use, which account for more than two-thirds of cases. We recently experienced a rare case of acute myeloid leukemia (AML) presenting with recurrent acute pancreatitis, which we later discovered was caused by diffusely infiltrating extramedullary sarcoma in the pancreas. Comprehensive analysis of previous cases of AML presenting as acute pancreatitis suggested involvement of cytogenetic alterations in chromosome 16 in its pathogenesis. Further improvement in management of acute pancreatitis is needed, and clinicians should note that this occasionally fatal condition can be the initial and only manifestation of AML. In practice, prompt initiation of intensive chemotherapy is critical for treating such cases of AML-induced acute pancreatitis.

Investigation of the mechanism of copy number variations involving the α-globin gene cluster on chromosome 16: two case reports and literature review.

Thalassemia is one of the most common single-gene disorder worldwide. An important genetic cause of thalassemia is copy number variations (CNVs) in the α-globin gene cluster. However, there is no unified summary and discussion on the detailed information and mechanisms of these CNVs. In this study, two novel CNVs, a tandem duplication (αααα159) and deletion (--259), were identified in two Chinese families with thalassemia patients, according to the results of hematologic analysis, routine genetic testing for thalassemia, multiplex ligation-dependent probe amplification (MLPA), next-generation sequencing (NGS) and other molecular methods. Co-inherited with ßCD41-42 mutation and --SEA deletion separately, αααα159 and --259 resulted in a patient with ß-thalassemia intermedia and a lethal fetus with Hb Bart's hydrops fetalis syndrome, respectively. Next, a literature review was performed to summarize all known CNVs involving the α-globin gene cluster. The molecular structure characteristics of these CNVs were analyzed and the possible mechanism was explored. It is the first time to analyze the generation mechanism of genome arrangements in the α-globin gene cluster systematically.

Characterizing Sleep Problems in 16p11.2 Deletion and Duplication.

Studies of 16p11.2 copy number variants (CNVs) provide an avenue to identify mechanisms of impairment and develop targeted treatments for individuals with neurodevelopmental disorders. 16p11.2 deletion and duplication phenotypes are currently being ascertained; however, sleep disturbances are minimally described. In this study, we examine sleep disturbance in a well-characterized national sample of 16p11.2 CNVs, the Simons Foundation Autism Research Initiative (SFARI) database of youth and adults (n = 692). Factor analyses and multilevel models of derived sleep questionnaires for youth (n = 345) and adults (n = 347) indicate that 16p11.2 carriers show elevated sleep disturbance relative to community controls. Non-carrier family members also show elevated sleep disturbance. However, sleep duration does not differ between carriers and controls. Further studies of sleep in 16p11.2 are needed.

Diversity of Clinical and Molecular Characteristics in Korean Patients with 16p11.2 Microdeletion Syndrome.

16p11.2 copy number variations (CNVs) are increasingly recognized as one of the most frequent genomic disorders, and the 16p11.2 microdeletion exhibits broad phenotypic variability and a diverse clinical phenotype. We describe the neurodevelopmental course and discordant clinical phenotypes observed within and between individuals with identical 16p11.2 microdeletions. An analysis with the CytoScan Dx Assay was conducted on a GeneChip System 3000Dx, and the sample signals were then compared to a reference set using the Chromosome Analysis Suite software version 3.1. Ten patients from six separate families were identified with 16p11.2 microdeletions. Nine breakpoints (BPs) 4-5 and one BP2-5 of the 16p11.2 microdeletion were identified. All patients with 16p11.2 microdeletions exhibited developmental delay and/or intellectual disability. Sixty percent of patients presented with neonatal hypotonia, but muscle weakness improved with age. Benign infantile epilepsy manifested between the ages of 7-10 months (a median of 8 months) in six patients (60%). Vertebral dysplasia was observed in two patients (20%), and mild scoliosis was noted in three patients. Sixty percent of patients were overweight. We present six unrelated Korean families, among which identical 16p11.2 microdeletions resulted in diverse developmental trajectories and discordant phenotypes. The clinical variability and incomplete penetrance observed in individuals with 16p11.2 microdeletions remain unclear, posing challenges to accurate clinical interpretation and diagnosis.

Language and Communication Deficits in Chromosome 16p11.2 Deletion Syndrome.

PURPOSE: Chromosome 16p11.2 deletion syndrome (OMIM #611913) is a rare genetic condition resulting from the partial deletion of approximately 35 genes located at Chromosome 16. Affected people exhibit a variable clinical profile, featuring mild dysmorphisms, motor problems, developmental delay, mild intellectual disability (ID), socialization deficits and/or autism spectrum disorder (ASD) traits, and problems with language. Specifically, a precise characterization of the speech, language, and communication (dis)abilities of people with this condition is still pending. METHOD: We used standardized tests and samples of naturalistic speech to provide a longitudinal profile of the speech, language, and communication problems of a boy with Chromosome 16p11.2 deletion syndrome and without ID or ASD. RESULTS: The proband shows impaired expressive abilities as well as problems with receptive language, dysprosody, and ASD-like communication deficits, such as impaired interactive skills, perseverative verbal behavior, overabundance of tangential responses, and lack of metapragmatic awareness and communicative use of gaze, meeting the criteria for social pragmatic communication disorder. CONCLUSIONS: Our results support the view that language and communication impairment should be regarded as one core symptom of Chromosome 16p11.2 deletion syndrome, even without a diagnosis of ASD or ID. Clinical implications of our results, with a focus on therapeutic interventions for children with 16p11.2 deletion syndrome and no ASD or ID, are also discussed. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21561714.

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism's common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.

Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific.

Sensory processing in 16p11.2 deletion and 16p11.2 duplication.

Deletions and duplications at the chromosomal region of 16p11.2 have a broad range of phenotypic effects including increased likelihood of intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), epilepsy, and language and motor delays. However, whether and how sensory processing is affected has not yet been considered in detail. Parents/caregivers of 38 children with a 16p11.2 deletion and 31 children with a 16p11.2 duplication completed the Sensory Behavior Questionnaire (SBQ) and the Child Sensory Profile 2 (CSP-2) along with other standardized questionnaires assessing autistic traits (SRS-2), ADHD traits (Conners 3), anxiety (SCAS-P) and adaptive behavior (VABS-3). SBQ and CSP-2 responses found that sensory processing differences were clearly evident in both 16p11.2 deletion and 16p11.2 duplication, though there was significant variation in both cohorts. SBQ data indicated the frequency and impact of sensory behavior were more severe when compared to neurotypical children, with levels being similar to autistic children. CSP-2 data indicated over 70% of children displayed clear differences in sensory registration (missing sensory input). Seventy-one percent with 16p11.2 duplications were also unusually sensitive to sensory information and 57% with 16p11.2 duplications were unusually avoidant of sensory stimuli. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with a 16p11.2 deletion and 16p11.2 duplication demonstrates that sensory processing differences have a profound impact on their lives.

Paternal uniparental disomy of chromosome 16 resulting in homozygosity of a GPT2 mutation causes intellectual and developmental disability.

Recessive mutations in glutamate pyruvate transaminase 2 (GPT2) have recently been found to be associated with intellectual and developmental disability (IDD). In this study, we discovered a homozygous missense variant, NM_133443: [c.1172C > T, p. Pro391Leu], of GPT2 on chromosome 16 in a proband diagnosed with IDD through trio whole-exome sequencing (WES). The pathogenicity of the variant was further verified by bioinformatics analysis and functional studies in vitro. This autosomal recessive disease was caused by paternal uniparental disomy (UPD) which was further proven by single nucleotide polymorphism array (SNP array). In past literature, recessive diseases in chromosome 16 were usually due to maternal UPD where Mendel's law of inheritance was not applicable. However, in our case we found that paternal UPD can cause recessive diseases related to the GPT2 gene on chromosome 16. Our study provides an important line of evidence for the diagnosis of GPT2-related intellectual developmental disorders.