Objective The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

ImportanceIt is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.ObjectiveTo evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.Design, Setting, and ParticipantsThis was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.ExposuresGenetic test results.Main Outcomes and MeasuresClinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.ResultsAmong 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).Conclusions and RelevanceResults of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

INTRODUCTION: There is overlap in the electroclinical features of many childhood epilepsy syndromes, especially those presenting with multiple seizure types, such as epilepsy with myoclonic-atonic seizures (EMAS) and Lennox-Gastaut syndrome (LGS). This study aimed to determine the frequency of diagnosis switching and the factors influencing epilepsy syndrome diagnosis in a cohort of children with possible EMAS, as well as to explore the relationship between epilepsy syndromes diagnoses, key electroclinical features, and clinically relevant outcomes. METHODS: This is a cross-sectional retrospective chart review of children treated at the Children’s Hospital of Colorado with a potential diagnosis of EMAS. RESULTS: There were 77 patients that met eligibility criteria, including 39% (n=30) with an initial diagnosis of EMAS and 74% (n=57) with a final diagnosis of EMAS. On average, for the 65% of patients who received more than one epilepsy diagnosis, the first, second, and third diagnoses were received within one year, three years, and ten years after epilepsy onset, respectively. Final diagnosis was significantly related to obtaining at least a six-month period of seizure freedom, p=0.03. Classic LGS traits, including paroxysmal fast activity, slow spike-and-wave, and tonic seizures were present in 50% of the overall cohort, although a minority of these patients had a final diagnosis of LGS. However, the presence of more LGS traits was associated with a higher likelihood of ongoing seizures. Adjusted for age of epilepsy onset, seizure freedom was half as likely for every additional LGS trait observed (0.49[0.31, 0.77], p=0.002). CONCLUSION: Current epilepsy syndrome classification has reduced applicability due to overlapping features. This results in diagnosis switching and limited prognostic value for patients with an overlapping clinical phenotype. Future studies should attempt to stratify patients based not only on epilepsy syndrome diagnosis, but also on the presence of various electroclinical traits to more accurately predict outcome.

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ABBREVIATIONS ACTHAdrenocorticotropic hormone CNV Copy number variant DEE Developmental and epileptic encephalopathy P/LP Pathogenic or likely pathogenic variant VUS Variants of uncertain significance WES Whole-exome sequencing AIM To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms.METHOD Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease. RESULTSLikely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology.INTERPRETATION This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. Highpriority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.

Split hand/foot malformation (SHFM) is a limb malformation with underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. There are six types of SHFM. Here, we report a boy with SHFM type 3 having normal 4th and 5th digits, absent 2nd and 3rd digits, and a 4th finger flexion deformity, as well as absent 2nd, 3rd and 4th toes bilaterally. His father, two paternal uncles, and two paternal first cousins have similar phenotype. Chromosome analysis showed a normal male karyotype. A 514 kb gain at 10q24.31–q24.32 (chr10:102,962,134–103,476,346, hg19) was identified using 6.0 Single nucleotide polymorphism (SNP) microarray, resulting in the duplication of nine genes, including BTRC and FBXW4. A detailed systematic review of literature and mapping of breakpoints using microarray data from all reported cases in PubMed and DECIPHER were conducted, and exon 1 of BTRC gene was identified as the critical region responsible for the SHFM3 phenotype. The potential mechanism and future studies of this critical region causing the SHFM3 phenotype are discussed.

The additional sex combs like (ASXL) gene family, comprised of the ASXL1, ASXL2, and ASXL3 genes, encodes proteins involved in epigenetic regulation, embryogenesis, and carcinogenesis. [1][2][3] Despite the implication of somatic ASXL mutations in a variety of malignancies, germline ASXL mutations do not appear to have an association with increased malignancy risk. Bainbridge-Ropers syndrome (BRPS) is a rare autosomal dominant genetic disorder with an estimated 89 known cases 4 that results from de novo ASXL3 gene mutations, 5 characterized by poor growth, hypotonia, intellectual disability, language delay, and dysmorphic facial features. 6 Many affected patients have autism disorder, and approximately one-third of patients have epilepsy. 7,8 The few published reports of cancer in patients with germline ASXL mutations are limited to patients with ASXL1 mutations, implicated in Bohring-Opitz syndrome (BOS), a phenotypically similar neurodevelopmental syndrome to BRPS. These include two patients with bilateral Wilms tumor, 9 and a father and son with identical germline ASXL1 mutations with acute myeloid leukemia. 10 Unlike BOS, there are no reported cases of malignancy in patients with BRPS. Here, we report the clinical course of a 3-year-old male with BRPS found to have precursor B-cell acute lymphoblastic leukemia (ALL).At age 10 months, the patient underwent neurologic evaluation due to developmental delay, feeding difficulties, and growth failure. He was hypotonic and had subtle dysmorphic features, including arched eyebrows and anteverted nares. A trio-based Autism/ID Xpanded Panel (GeneDx, LLC 2019) sent with samples from biological parents demonstrated a de novo pathogenic variant (c.4678C>T; p.R2560X) in the ASXL3 gene (RefSeq transcript NM_030632.1, human genome build GRCH37/UCSC hg19), consistent with BRPS.At age 3 years, he presented with feeding intolerance, fatigue, and abdominal pain. Laboratory analysis showed white blood cells (WBCs) 12.7/mm 3 with 27% peripheral blasts, hemoglobin 8.3 g/dl, and platelet count 69,000/mm 3 . Peripheral flow cytometry identified an immature lymphoid population, consistent with precursor B-cell ALL (Table 1).Bone marrow analysis revealed no detectable clonal abnormalities on standard cytogenetics, and fluorescence in situ hybridization (FISH)

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