PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

Background ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans. Methods To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. Results We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. Conclusion Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

We present three children from two unrelated families with Angelman syndrome (AS) whose developmental skills are far more advanced than any other non-mosaic AS individual ever reported. All have normal gait and use syntactic language spontaneously to express their needs. All of them have a c.2T > C (p.Met1Thr) variant in UBE3A, which abrogates the start codon of isoform 1, but not of isoforms 2 and 3. This variant was maternally inherited in one set of siblings, but de novo in the other child from the unrelated family. This report underscores the importance of considering AS in the differential diagnosis even in the presence of syntactic speech.

3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next‐generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC‐ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC‐ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next‐generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.

Introduction: 3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Methods: Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next generation phenotyping platform Face2Gene (FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls, using a proprietary algorithm. Area under the curve of receiver operating characteristic curves (AUC-ROC) were used to determine the capacity of Face2Gene to identify 3q29del cases against controls. Results: In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006). Conclusion: This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.