Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway.

BACKGROUND: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature. METHODS: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X-inactivation). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants. RESULTS: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo. CONCLUSION: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.

De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Racial differences in the dermatological manifestations of tuberous sclerosis complex and the potential effects on diagnosis and care.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder of non-malignant tumor growths throughout major organ systems and neurological, neuropsychiatric, renal, and pulmonary co-morbidities. Skin manifestations are readily visible, often develop early in life, and are major features that contribute to TSC diagnosis. Medical photographs of such manifestations are commonly shown as examples from White individuals creating a potential barrier to accurately identifying these features in darker skinned individuals. Objectives: The aim of this report is to raise awareness of dermatological manifestations associated with TSC, compare their appearance by race, and consider how recognition of these features could impact diagnosis and treatment of TSC. Design and Methods: We conducted a retrospective chart review at the TSC Center of Excellence (TSCOE) at the Kennedy Krieger Institute, which included all patients in the center from 2009 (inception) through the end of the calendar year 2015 and analyzed data from the TSC Alliance Natural History Database (NHD). Results: Among TSCOE patients, 50% of Black patients were diagnosed before the age of 1 year, compared with 70% of White patients. NHD data corroborated this trend showing a significant difference with only 38% of Blacks as compared with 50% of Whites were diagnosed at age ⩽1 year. A significant difference was observed where White participants had higher odds of having received genetic testing in both data sets. While no differences in the total number of TSC features was observed in either data set, shagreen patches and cephalic fibrous plaques were more frequently recorded in the NHD for Black individuals. Conclusion: We highlight a disparity in the representation of Black participants within the NHD, TSCOE, and TSC trials, in addition to differences in utilization of molecular testing and topical mechanistic target of rapamycin (mTOR) inhibitor therapy between Black and White individuals. We show a trend toward later diagnosis age in Black individuals. These differences between races warrant further study across additional clinical sites and other minority groups.

Differences in skin manifestations between races in individuals with tuberous sclerosis complex and the potential effects of these differences on diagnosis and care Background: To our knowledge, tuberous sclerosis complex (TSC) does not affect races at different frequencies; however, observations in clinical settings anecdotally, and results from research studies, suggest a disparity in the representation and diagnosis of Black individuals with TSC. Historically, it has been noted that TSC facial features, such as angiofibromas, present differently in individuals with darker skin tones and are often misdiagnosed leading to delays in TSC diagnosis and treatment. Objectives: The aim of this publication is to identify differences in TSC skin features between Black and White individuals to raise awareness in the clinics and community. In addition, we provide insight into how these differences can affect the timing of TSC diagnosis and subsequent treatment regimens. We aim to highlight these potential disparities to ensure improved timing in diagnosis and treatment regimens for all affected by TSC in the future. Design and Methods: Differences between Black and White individuals with TSC were observed looking at historical medical data collected at a TSC Center of Excellence (TSCOE) on all patients seen in the center from 2009 through the end of 2015 and in the TSC Alliance Natural History Database (NHD) that has been collecting clinical data on individuals with TSC since 2006. Results: We observed that Black individuals are less likely to be diagnosed at ⩽1 year of age as compared with White individuals within the NHD. Data from the TSCOE support these findings but were not statistically significant. We observed a difference in NHD participation with only 150 Black individuals participating, representing 6% of total NHD participants. Our data indicate a difference between Black and White individuals both in the TSCOE and NHD showing that Black individuals are less likely to receive genetic testing, utilize topical mTOR therapy, and participate in TSC clinical trials. Conclusion: Given the observed trends, outreach and education to clinicians and other healthcare providers is needed to inform of these differences. Given that skin manifestations play an essential role in early recognition of TSC and timely referral to TSC specialists, we hope these data lead to improvement in the recognition of TSC in darker skinned individuals at earlier ages, thus improving clinical outcomes associated with TSC manifestations by optimizing treatment early in life.

A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.

PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation. METHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. RESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding. CONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.