Faculty Bibliography

Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.

Congenital diaphragmatic hernia (CDH) in neonates may occur as an isolated finding, in association with other anomalies, or as part of a genetic syndrome. We report the first case of an infant with CDH who presented with hyponatremic seizures due to adrenal hypoplasia congenita (AHC). The patient underwent repair of CDH defect. After an uncomplicated postoperative course while on discharge planning, he developed a seizure episode associated with severe hyponatremia and hyperkalemia. Extensive diagnostic workup revealed an NR0B1 gene variant confirming the diagnosis of X-linked AHC. The patient was eventually discharged home on hydrocortisone, fludrocortisone, and salt supplements. There are a few case reports of adrenal insufficiency in neonates with CDH, manifesting with symptoms before and immediately after reparative surgery. Clinical presentation of our patient was unique in manifesting as neonatal seizure secondary to severe hyponatremia after a stable postoperative phase. The patient's electrolytes and hemodynamic status remained stable before, during, and after surgery for CDH. This case underlines the importance of taking detailed family history and continued vigilance for signs and symptoms of adrenal insufficiency in infants with repaired CDH by pediatricians and intensivists.

PURPOSE/OBJECTIVE:To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS:Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS:The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION/CONCLUSIONS:We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

The GATA zing finger domain-containing protein 2B (GATAD2B) gene encodes the p66beta protein, a subunit of the MeCP1-Mi2/ nucleosome remodeling and deacetylase complex, which is involved in transcription regulation and chromatin remodeling. Pathogenic variants in the GATAD2B gene have recently been associated with a recognizable neurodevelopmental syndrome, characterized by intellectual disability, limited speech, childhood hypotonia, and dysmorphic features. The majority of reported patients resulted from de novo loss of function (LOF) variants. We report a patient identified through whole exome sequencing analysis where a healthy mother was found to be low level mosaic for the pathogenic LOF variant found in her child, who is affected with GATAD2B-associated neurodevelopmental disorder (GAND). This variant was only found with the use of next generation sequencing technology in the mother and confirmed by digital droplet PCR. We summarize additional patients with GATAD2B LOF variants from a literature review and with our patient we contribute to delineate the phenotypic spectrum of GAND. We highlight the importance of detailed genetic testing, testing method, and counseling for cases of somatic mosaicism in an unaffected parent of children with GAND. This inheritance may be underreported and has a direct impact on reproductive planning and prenatal diagnosis.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.

Background:Y chromosome material is detected in 6% of Turner syndrome patients by karyotype (1). Y/autosome translocation in Turner syndrome is associated with a) female genitalia or signs of virilization; b) gonadal dysgenesis and a 7-30% future risk of gonadoblastoma (2). We present an atypical phenotype of a Turner syndrome female with 45,X/45,X,dic(Y;5)(p11.3; p15.3). Clinical case: A 9-year and 10-month-old girl presented with short stature (height: 121 cm, -3.2 SD; weight: 37.6 kg, 75%) and Turner syndrome habitus: wide short neck, broad chest, with no signs of virilization, no cardiac defects, no hepatosplenomegaly and with mild learning disability. Lab evaluation: LH 1.14 (<=2.91 U/L); FSH 50.9 (0.72-5.33 U/L); estradiol <2 (

EMBASE:617153110

ISSN: 0163-769x

CID: 2631962