Genotype and Phenotype in 12 additional individuals with SATB2-Associated Syndrome

SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible

Mutations in GABRB3

Objective: To examine the role of mutations in GABRB3 encoding the b3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands frommultiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy withmyoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant beta(3), together with alpha(5) and gamma(2s) subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Detection of mutually exclusive mosaicism in a girl with genotype-phenotype discrepancies

Discordance between clinical phenotype and genotype has multiple causes, including mosaicism. Phenotypes can be modified due to tissue distribution, or the presence of multiple abnormal cell lines with different genomic contributions. We have studied a 20-month-old female whose main phenotypes were failure to thrive, developmental delay, and patchy skin pigmentation. Initial chromosome and SNP microarray analysis of her blood revealed a non-mosaic ∼24Mb duplication of 15q25.1q26.3 resulting from the unbalanced translocation of terminal 15q to the short arm of chromosome 15. The most common feature associated with distal trisomy 15q is prenatal and postnatal overgrowth, which was not consistent with this patient\u27s phenotype. The phenotypic discordance, in combination with the patchy skin pigmentation, suggested the presence of mosaicism. Further analysis of skin biopsies from both hyper- and hypopigmented regions confirmed the presence of an additional cell line with the short arm of chromosome X deleted and replaced by the entire long arm of chromosome 15. The Xp deletion, consistent with a variant Turner Syndrome diagnosis, better explained the patient\u27s phenotype. Parental studies revealed that the alterations in both cell lines were de novo and the duplicated distal 15q and the deleted Xp were from different parental origins, suggesting a mitotic event. The possible mechanism for the occurrence of two mutually exclusive structural rearrangements with both involving the long arm of chromosome 15 is discussed

Phenotypic and imaging spectrum associated with WDR45

Background Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5 (NBIA5). Global developmental delay is seen at an early age with a slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. Methodology We present 17 new cases and reviewed 106 reported cases of NBIA5. Detailed information related to developmental history and key time to event measures was collected. Results Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. While most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted half of our cohort and was associated with an older age of image acquisition, while myelination abnormalities were associated with a younger age. Conclusions WDR45 is a progressive and evolving disorder, which is often delayed in diagnosis. Developmental delay and seizures predominate early childhood, followed by a progressive decline of neurologic function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.Peer reviewe

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features.

Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects

Randomized clinical trial of first‐line genome sequencing in pediatric white matter disorders

Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.A prospective time-delayed cross-over design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between 12/01/2015 - 09/27/2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for four months followed by GS.34 individuals were assessed at interim review. The genetic origin of two patient's leukoencephalopathy was resolved before randomization. Nine patients stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the Immediate (5 of 9 [56%] vs. 0 of 9 [0%]; Wild-Seber