Neda Zadeh

De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay

Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.

Ectopia lentis as the presenting and primary feature in Marfan syndrome.

Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease‐causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohorts mutations occurred in the 5′ portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype–phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life‐threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

Diagnosis and management of familial Mediterranean fever: integrating medical genetics in a dedicated interdisciplinary clinic.

Familial Mediterranean fever is an autosomal recessive genetic disorder characterized by recurrent febrile polyserositis, especially prevalent in individuals of Mediterranean descent. Familial Mediterranean fever can have nonspecific manifestations that mimic many common acquired disorders such as infections, acute appendicitis, cholecystitis, and arthritis, which can delay diagnosis for many years and subject patients to extensive evaluations and even unnecessary surgery. Untreated familial Mediterranean fever can result in serious complications such as end-stage renal disease and malabsorption secondary to amyloid deposition in the kidneys and digestive tract, male and female infertility, and growth retardation in children. These significant sequelae, along with the episodic acute attacks, are readily preventable by treatment with oral colchicine and underscore the necessity of early detection and treatment from a medical, psychosocial, and economic standpoint. We describe our comprehensive approach to the accurate diagnosis and effective management of this disorder by means of a dedicated familial Mediterranean fever clinic that incorporates medical genetics on equal footing with general medicine. In addition to providing the clinician with the presenting features of familial Mediterranean fever, methods of diagnosis including molecular testing, and current management based on our extensive experience with hundreds of affected individuals, we also advance this approach as a model for the incorporation of medical genetics practice into the more traditional domains of general medicine.

Nuchal translucency measurement in fetuses with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder with a high carrier frequency in the general population. The severity of this disorder indicates the importance of early prenatal detection. In medical literature, there are a few published case reports of enlarged nuchal translucency (NT) measurement in association with a diagnosis of SMA in the fetus. Our goal is to determine whether SMA in infants is associated with a history of an increased NT measurement during pregnancy.

De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects

The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman‐Rett‐Prader‐Willi Consortium and others have documented genotype–phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non‐deletion AS cases, and therefore examined body mass measures in a cohort of non‐deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age‐ and gender‐appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre‐obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity.

IL-1 blockade as a novel approach to treatment of hyperzincemia and hypercalprotectinemia, a possible new autoinflammatory syndrome

Methods We describe a patient initially evaluated at 10 months of age for gross developmental delay, failure to thrive, splenomegaly, and microcytic anemia. Physical exam was significant for weight <3rd percentile, splenomegaly (down 5cm), and head lag. Initial laboratories revealed microcytic anemia (hemoglobin 8.7 g/dL); elevated platelets 499 K/uL, C-reactive protein 23.2 mg/dL (<0.2) and erythrocyte sedimentation rate 120 mm/h (0-10). Radiographs showed Erlenmeyer flask deformities of the femurs. Workup for lysosomal storage disorders, oncologic processes, and infections were negative. Genetic testing of known mutations in FAS, CIAS1, ELA2, LPIN2, MVK, PSTPIP1, and TNFRSF1A were negative. Immunoglobulins were elevated with normal T and B cells. On further workup for failure to thrive, a plasma zinc level was found elevated at 532 mcg/dL (60-120). Due to his persistently inflamed state, there was concern for hyperzincemia related to hypercalprotectinemia. Calprotectin level, measured by enzyme-linked immunosorbent assay, was elevated: 428,300 ng/mL (<420). On the basis of these findings the diagnosis of hyperzincemia associated with hypercalprotectinemia was made (OMIM 194470). Additionally, the patient’s workup has revealed the following mutations with unknown clinical significance: a heterozygous variant in the MEFV gene (T577A), a hemizygous duplication of exons 61-79 of the dystrophin gene (CPK normal), and a maternally inherited microduplication at Xp21.2. Colchicine was started due to the MEFV gene mutation with little to no improvement. Based on calprotectin’s role in inflammation, and possible link to IL-1, anakinra was initiated.