Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.

Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Tatton-Brown-Rahman syndrome: Six individuals with novel features.

Tatton-Brown Rahman syndrome (TBRS) is an overgrowth-intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy-eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T-cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.

Clinical delineation of GTPBP2-associated neuro-ectodermal syndrome: Report of two new families and review of the literature.

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

Cost-Effectiveness of Universal or High-Risk Screening Compared to Surveillance Monitoring in Autism Spectrum Disorder.

The American Academy of Pediatrics recommends universal screening for autism spectrum disorder at 18 and 24 months. This study compared the cost-effectiveness of universal or high-risk screening to surveillance monitoring. Simulation models estimated the costs and outcomes from birth to age 6 years. The incremental cost per child diagnosed by 36 months was $41,651.6 for high-risk screening and $757,116.9 for universal screening from the societal perspective. Universal screening may not be a cost-effective approach to increase earlier treatment initiation, as most children initiated treatment after age 60 months. Eliminating wait times resulted in more children initiated treatment by 48 months, but at a high initial cost that may be offset by future cost-savings related to better outcomes.

Noncompaction cardiomyopathy in an infant with Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is a rare autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in α-dystroglycan glycosylation have been implicated in the aetiology of WWS. We describe a patient with nonclassical features of WWS presenting with heart failure related to noncompaction cardiomyopathy resulting in death at 4 months of age. Muscle biopsy revealed absent α-dystroglycan on immunostaining and genetic testing confirmed the diagnosis with two previously described POMT2 mutations. This is the first reported case of WWS syndrome associated with noncompaction cardiomyopathy.

PLS3 Mutations in X-Linked Osteoporosis: Clinical and Bone Characteristics of Two Novel Mutations.

BACKGROUND AND OBJECTIVES: Plastin 3 (PLS3) mutations are associated with an X-linked osteoporosis. Here we describe two new families with novel mutations, including one with a whole gene PLS3 deletion, and review the literature on 9 previously reported cases. RESULTS: Hemizygous male carriers presented with multiple peripheral bone fractures, low bone mineral density (BMD), and vertebral compression fractures. Heterozygous female carriers did not have a history of fragility fractures, although 1 individual presented with low BMD. Apart from greyish-tinged sclera, no other extraskeletal features of osteogenesis imperfecta were identified. Histomorphometry from a transiliac bone biopsy in one of our index patients demonstrated significantly low trabecular bone volume with increased bone turnover. Bisphosphonate treatment was associated with a reduction in the fracture rate and increased bone density. CONCLUSION: Hemizygous mutations in PLS3 may cause a monogenic form of X-linked osteoporosis presenting in childhood with a nonspecific phenotype. No characteristic ocular, dental, or joint abnormalities are defined. When genetic testing is undertaken to investigate for primary causes of bone fragility, we suggest PLS3 be included in order not to miss this diagnosis.

Identification of a homozygous missense mutation in LRP2 and a hemizygous missense mutation in TSPYL2 in a family with mild intellectual disability.

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

Middle and inner ear malformations in mutation-proven branchio-oculo-facial (BOF) syndrome: case series and review of the literature.

Hearing impairment is common in individuals with branchio-oculo-facial (BOF) syndrome. The majority of described individuals have conductive hearing impairment due to malformed ossicles and/or external canal stenosis or atresia, although a sensorineural component to the hearing impairment in BOF syndrome is increasingly being reported. Sophisticated computed tomography (CT) of the temporal bone has revealed middle and inner ear malformations in three previous reports. We present middle and inner ear abnormalities in three additional individuals with mutation-proven BOF syndrome. We suggest that temporal bone CT imaging be included in the medical workup of a child with BOF syndrome, in order to guide management.

A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies.

We present two unrelated male infants with strikingly similar clinical features which have not previously been reported together. The most unusual feature was the presence of multiple small capillary malformations (port-wine stains) on the skin from birth. Both infants had intractable seizures, microcephaly with progressive cortical atrophy, severe developmental delay, dysmorphic facial features, and hypoplasia of the distal phalanges. To our knowledge, no other person with this unique constellation of features has been described.

Trisomy 9p and Prader-Willi syndromes in an infant resulting from a de-novo unbalanced t(9;15) translocation.

Trisomy 9p is a well-described dysmorphic syndrome. The physical features include hypertelorism, down-slanting palpebral fissures, deep-set eyes, down-turned corners of the mouth, and mild skeletal anomalies including hypoplastic terminal phalanges. We report an infant born with some of the typical features of trisomy 9p syndrome, as well as additional features that include extreme joint hyperlaxity with subluxation of the knees and elbows, arachnodactyly, and total anomalous pulmonary venous return. The karyotype revealed an unbalanced chromosome complement. Specifically, a derivative chromosome from a de-novo unbalanced translocation of chromosomes 9 and 15 resulted in partial trisomy of 9pter to 9q13 and deletion of the long arm of chromosome 15 proximal to band q13. Fluorescence in-situ hybridization studies and methylation analysis by Southern blotting revealed deletion of the SNRPN locus on the paternally derived chromosome 15, consistent with Prader-Willi syndrome. This infant represents the first reported case of trisomy 9p syndrome with total anomalous pulmonary venous return and hypoplasia of the amygdala and hippocampus, with the additional finding of Prader-Willi syndrome resulting from a derivative chromosome arising from an unbalanced de-novo t(9;15) translocation.

Further clinical delineation of the Börjeson-Forssman-Lehmann syndrome in patients with PHF6 mutations.

Börjeson-Forssman-Lehmann syndrome is an X-linked condition caused by PHF6 mutations. The classical description of males with this disorder includes severe intellectual disability with epilepsy, microcephaly, short stature, obesity, hypogonadism, and gynecomastia. We present three males with PHF6 mutations whose features included deep-set eyes, large ears, coarse face, tapering fingers, and truncal obesity. Unlike the original description of the syndrome; however, the males described herein had varying degrees of intellectual disability and hypogonadism, were of normal to tall stature, had normal to large head sizes, and did not have seizures. This departure from the usual clinical description of Börjeson-Forssman-Lehmann syndrome is consistent with recent reports of males with mutations in PHF6. In addition, we describe the phenotype and X-inactivation pattern in two females heterozygous for PHF6 mutations, both of whom have mild features of the syndrome.