ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Delineation of the 9q31 deletion syndrome: Genomic microarray characterization of two patients with overlapping deletions.

Interstitial deletions of chromosome 9q31 are very rare. The deletions in most reported patients have been detected by conventional cytogenetics, with reported breakpoints ranging between 9q21 and 9q34. Therefore, an accurate description of a "9q31 deletion syndrome" could not be established. However, based on microarray studies, a small region of overlap has recently been proposed. We report clinical features of two unrelated individuals with overlapping 9q deletions identified by SNP microarray analysis. Patient 1 has a 9 Mb deletion, while Patient 2's deletion was 21.6 Mb. The clinical features common to our patients and those in the literature include developmental delay and short stature. Patient 2 shows additional features not reported in other 9q31 deletions, such as hearing loss, ventriculomegaly, cleft lip and palate, and small kidneys, which could be due to the larger size of the deletion, hence the influence of the genes in the region beyond the smallest region of overlap. Based on the comparison of these patients with the previously reported patients, we redefine the smallest region of overlap and characterize the clinical features of the 9q31 deletion syndrome.

A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.

Neuroradiographic findings in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.

New recessive truncating mutation in LTBP3 in a family with oligodontia, short stature, and mitral valve prolapse.

Latent TGFB-binding protein 3 (LTBP3) is known to increase bio-availability of TGFB. A homozygous mutation in this gene has previously been associated with oligodontia and short stature in a single family. We report on two sisters with homozygous truncating mutations in LTBP3. In addition to oligodontia and short stature, both sisters have mitral valve prolapse, suggesting a link between truncating LTBP3 mutations and mitral valve disease mediated through the TGFB pathway.

7q11.23 Duplication syndrome: Physical characteristics and natural history.

In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7.

Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature.

BACKGROUND: There are only ten reported cases of interstitial deletions involving cytogenetic bands 10q21.3q22.2 in the literature. Of the ten patients with overlapping 10q21.3q22.2 interstitial deletions, only nine have been characterized by chromosomal microarray analysis. Here, we report a two-and-a-half-year-old patient with a de novo 10.2-Mb deletion that extends from 10q21.3 to 10q22.3 and contains 92 protein coding genes. CASE PRESENTATION: The patient is the product of a 37-week dizygotic twin pregnancy and presented with global developmental delay, hypotonia, feeding difficulties, short stature, poor weight gain, scaphocephaly, retrognathia, hypoplasia of the optic nerves/chiasms, a distinctive facial gestalt, as well as additional minor dysmorphic features. The deletion identified in our patient is the second largest reported interstitial deletion involving the 10q21.3q22.2 region. Our patient presents with the generalized features observed in 10q21.3q22.2 deletion patients and also presents with several novel findings including scaphocephaly, hypoplasia of the optic nerves and chiasms, and a very distinctive facial gestalt. CONCLUSIONS: Based on a literature review, we identify a commonly deleted region and suggest that KAT6B is a critical gene within the 10q21.3q22.2 region. However, a review of the reported overlapping deletions also suggests that there are additional critical genes contributing to the clinical presentation of these patients.

De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder.

De novo variants of ASH1L, which encodes a histone methyltransferase, have been reported in a few patients with intellectual disability and autistic features. Here, we identified a novel de novo frame-shift variant, c.2422_2423delAAinsT which predicts p.(Lys808TyrfsTer40), in ASH1L in a patient with multiple congenital anomalies (MCA), fine motor developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea, and scoliosis. This frame-shift variant is expected to result in loss-of-function. Our report provides further evidence to support loss-of-function alterations of ASH1L as causative for an emergent neurodevelopmental syndrome characterized by MCA, intellectual disability, and behavioral problems, and further delineates this genetic disorder.

Intracranial Calcifications in Young Children.

Intracranial calcifications in young infants, while suggesting intrauterine infections, can also be due to numerous other conditions, including rare genetic disorders. We describe 2 children in whom the presence and pattern of intracranial calcifications led to the diagnosis of uncommon genetic disorders, Adams-Oliver syndrome and Aicardi-Goutieres syndrome. Differentiating genetic conditions from intrauterine infections or other causes of intracranial calcifications enables practitioners to provide accurate counseling regarding prognosis and recurrence risk.