Golder N. Wilson

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.

Anomalies associated with gastroschisis and omphalocele: Analysis of 2825 cases from the Texas Birth Defects Registry

BACKGROUND/PURPOSE The increasing prevalence of abdominal wall defects prompted analysis of anomalies associated with gastroschisis and omphalocele in the Texas Birth Defects Registry (TDBR). METHODS Cases of gastroschisis (ICD9 code 756.71), omphalocele (756.70), and/or unspecified anomalies of the abdominal wall (756.79) were obtained from the TDBR after IRB approval and analyzed using Microsoft Access© and Excel© databases. RESULTS Analysis began with 2825 cases including 1831 of gastroschisis, 814 of omphalocele, and 180 of unspecified abdominal wall defects plus 9680 associated anomalies that were classified according to system. The overall prevalence of abdominal wall defects among 3,806,299 Texas births from 1999 to 2008 was 7.4 per 10,000 with 4.8 per 10,000 for gastroschisis and 2.1 for omphalocele. After excluding ambiguous cases (8.5% possibly misclassified), anomaly spectra were similar for the two AWD with musculoskeletal (limb contractures or defects), cardiovascular, gastrointestinal, urogenital, and central nervous system defects being most common. Of 1831 cases with gastroschisis, 594 (32%) had associated anomalies compared to 654 (80%) of 814 omphalocele cases. CONCLUSIONS Gastroschisis as well as omphalocele has significant associated anomalies that are important to appreciate during pre- and postnatal management.

Interstitial deletion 5q14.3q21.3 with MEF2C haploinsufficiency and mild phenotype: when more is less.

An 18‐year‐old female with mild mental disability (global IQ 69), febrile seizures with subsequent myoclonic/grand mal epilepsy, and subtle morphologic changes is described with del 5(q14.3q21.3) by karyotype and minimal DNA deletion of 21.08 Mb by array comparative genomic hybridization microarray analysis (arr chr5:83,592,798‐104,671,993 X1) that encompasses at least 50 genes. Included in the deletion interval is the MEF2C gene that usually causes severe mental disability when haploinsufficient, illustrating the complexity of clinic–cytogenetic correlation even with defined segmental aneuploidy. Interaction of MEF2C with the deleted febrile seizure (FEB4) and juveline myoclonic epilepsy (EJM4) loci plus the G‐protein receptor (GPR98/MASS1/Usher syndrome) gene may moderate the phenotype, perhaps through common regulation by calcium.

Registry analysis supports different mechanisms for gastroschisis and omphalocele within shared developmental fields

Nine thousand two hundred eighty abnormalities associated with 2,943 abdominal wall defects (AWD) encoded from 1999 to 2008 by the Texas Birth Defects Registry (TBDR) were classified and analyzed for mechanism, beginning with 1,831 gastroschisis cases, 774 (41%) with 2,368 associated anomalies (AA) and 814 of omphalocele, 727 (89%) with 4,092 AA. Typical AA profiles for Trisomy 18 (23% of omphalocele cases) and Beckwith–Wiedemann syndrome (15%) validated registry AA descriptors, chromosome disorders surprisingly accounting for 24% of known conditions with gastroschisis followed by expected amniotic band (ADAM) complex (23%) and amyoplasia/arthrogryposis (16%). Separation of known diagnoses, fetal‐stillbirth cases, and transitional or secondary AA left 330 cases of gastroschisis with 594 AA (452 major, 142 minor) and 295 cases of omphalocele with 956 AA (683 major, 273 minor). Anomalies suggestive of vascular origin (intestinal atresias, amyoplasia, bands) were more frequent with gastroschisis and those of defective lateral folding (exstrophies, limb‐body wall defects) with omphalocele. Most AA favoring omphalocele had parallel frequencies with gastroschisis, whether by system/region—for example, cardiac AA (10% of cases), contractures (4.7%), limb (3.7%), CNS (3.2%) for gastroschisis versus cardiac (35%), contractures (14%), digestive‐excretory‐trunk‐axial (all ∼11%), CNS (9.9%) for omphalocele—or for particular minor/major AA—for example, micrognathia (0.72% versus 3.3%), spina bifida (0.59% versus 3.9%), anal atresia (0.73% versus 6.4%), two‐vessel cord (0.22% versus 5.6%). Similar frequencies of many AA reflective of early patterning support common AWD origin within early developmental fields and reinforce the use of large birth defect numbers from suitably qualified registries to define anomaly mechanism as well as prevalence.

Al‐Awadi/Raas‐Rothschild/Schinzel (AARRS) phocomelia syndrome: Case report and developmental field analysis

We describe a girl infant with anomalies of the left pelvis and lower limb (pelvic, femoral, and tibial hypogenesis with absent fibula), subtle facial changes, patent foraman ovale, single umbilical artery, single kidney, and imperforate anus. The external genitalia were asymmetric and ambiguous with normal uterus and ovaries visualized by ultrasound. The anomalies are compatible with previously reported cases of Al‐Awadi/Raas‐Rothschild/Schinzel (AARRS) phocomelia, an autosomal recessive disorder with WNT7 gene mutations documented in one family. We suggest that AARRS phocomelia, Fuhrmann syndrome, and similar conditions comprise a spectrum, and that the anomaly pattern derives from serial action of the same signal pathways within primary (e.g., the major axes), secondary (e.g., heart or limb primordia), and/or local (e.g., tibial–fibular differentiation) developmental fields.

Autism spectrum disorder with microdeletion 10q26 by subtelomere FISH

An 11-year-old female with early feeding problems, mild motor delays, normal speech, subtle facial changes, social difficulties, anxiety and a diagnosis of Asperger disorder was found to have deletion of 10q26.3 by subtelomere fluorescent in situ hybridization (stF) analysis. Our patient and others with 10q26 aneuploidy add this region to 11 other autism susceptibility loci qualified by converging genome linkage/association, high resolution chromo - some, and mutation studies in our review. We summarize these loci and the current spectrum of terminal 10q deletion cases.

Chromosome Xq13.2 Microduplication Involving an X-Inactivation Gene in a Girl with Short Stature, Madelung Deformity, and von Willebrand Disease

BACKGROUND The objective of the study was to describe a novel Xp13.2 chromosome microduplication in a child with some features of Turner syndrome but with menorrhagia after normal menarche. We used clinical evaluation and high resolution chromosome (microarray) analysis. CASE A 15-year-old girl with typical (short stature, pulmonic stenosis, widely-spaced nipples) and atypical (Madelung deformity, menorrhagia) manifestations of Turner syndrome had a novel chromosome constitution with extra material (microduplication) at band Xq13.2 that contained the X-inactive-specific-transcript locus. She also had connective tissue laxity, suggestive of vessel fragility as a contributor to her menorrhagia as well as her diagnosis of von Willebrand disease. This first case of selective X-inactive-specific-transcript locus duplication suggests a role for gene repression in Turner syndrome and other disorders that affect ovarian function. CONCLUSION High-resolution chromosome (microarray) analysis, now a standard of care, will provide new insights into adolescents with abnormal growth and reproductive tract symptoms, especially when accompanied by congenital anomalies.

KCNK9 imprinting syndrome—further delineation of a possible treatable disorder

Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore‐ domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab–Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab–Israeli family and suggest this may be a treatable disorder.

Inaccuracy of non-invasive prenatal screening demands cautious counsel and follow-up.

Conflicts of interest: None. Correspondence to: Golder N. Wilson, M.D., Ph.D., Department of Pediatrics, Texas Tech University Health Science Center, Lubbock and Medical City Hospital, 5347 W Mockingbird, Dallas, TX 75209. E-mail: golder.wilson@ttuhsc.edu Article first published online in Wiley Online Library (wileyonlinelibrary.com): 28 December 2015 DOI 10.1002/ajmg.a.37530 How to Cite this Article: Tonk VS, Wilson GN. 2016. Inaccuracy of non-invasive prenatal screening demands cautious counsel and follow-up.

Array-Comparative Genomic Hybridization/Microarray Analysis: Interpretation of Copy Number Variants

Two revolutionary advances in molecular biology have enabled scanning of the entire human genome for genetic variation: 1. Array-comparative genomic hybridization-microarray analysis (aCGH, CMA, microarray analysis, referred to henceforth as aCGH) that identifies altered DNA dosage. 2. Whole genome or exome sequencing (WGS or WES) that identifies nucleotide sequence changes.