The recurrent TUBB3 Gly98Ser substitution is the first described to inconsistently result in CFEOM3.

Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C.

A specific mutation in TBL1XR1 causes Pierpont syndrome.

Background: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome.

Methods: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals.

Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD).

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear.

Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome.

Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications.

Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.

Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA.

Occurrence of nephroblastomatosis with dup(18)(q11.2-q23) implicates trisomy 18 tumor screening protocol in select patients with 18q duplication.

Duplications of the long arm of chromosome 18 have been previously reported in patients with phenotypic findings similar to full trisomy 18. Trisomy 18 increases the risk for Wilms tumor and it is currently recommended that these patients undergo abdominal ultrasonography screening every 6 months. We report on nephroblastomatosis in a 27-month-old male with a 55 Mb duplication of chromosome 18q11.

Report of a patient with developmental delay, hearing loss, growth retardation, and cleft lip and palate and a deletion of 7q34-36.1: review of distal 7q deletions.

The use of aCGH has improved our ability to find subtle cytogenetic abnormalities as well as to find more precise information in patients with previously known abnormalities. In addition, it has allowed more specific genotype-phenotype correlation. In this report we describe a patient with a chromosomal deletion initially diagnosed with conventional cytogenetic analysis which was redemonstrated and more specifically described upon aCGH analysis.

Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency.

Context: Mutations in the electron donor enzyme P450 oxidoreductase (POR) result in congenital adrenal hyperplasia with apparent combined 17α-hydroxylase/17,20 lyase and 21-hydroxylase deficiencies, also termed P450 oxidoreductase deficiency (PORD). Major clinical features present in PORD are disordered sex development in affected individuals of both sexes, glucocorticoid deficiency, and multiple skeletal malformations.

Objective: The objective of the study was to establish a noninvasive approach to prenatal diagnosis of PORD including assessment of malformation severity to facilitate optimized prenatal diagnosis and timely treatment.

Four new patients with Gomez-Lopez-Hernandez syndrome and proposed diagnostic criteria.

Gomez-Lopez-Hernandez syndrome (GLHS) is a rare neurocutaneous disorder. We are aware of thirty previously reported cases. We present four additional patients with this condition.

SMARCAL1 deficiency predisposes to non-Hodgkin lymphoma and hypersensitivity to genotoxic agents in vivo.

Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder with prominent skeletal, renal, immunological, and ectodermal abnormalities. It is caused by mutations of SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response protein. To determine the relationship of this function to the SIOD phenotype, we profiled the cancer prevalence in SIOD and assessed if defects of nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), respectively, explained the ectodermal and immunological features of SIOD.

Characterization of six novel patients with MECP2 duplications due to unbalanced rearrangements of the X chromosome.

Males with duplication of the Xq28 region, including methyl CpG-binding protein 2 (MECP2), exhibit a characteristic phenotype, including developmental delay, intellectual disability, limited or absent speech, limited or absent ambulation, and recurrent respiratory infections. We report six males with MECP2 duplications identified using array comparative genomic hybridization. The minimal sizes of these duplications range from ∼0.

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.

Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.

Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.

Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia.

De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction.

Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut, and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.

Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE.

Objective: To characterise genetic and clinical findings in patients with ZIC2 mutations.

Inherited 14q duplication and 21q deletion: a rare adjacent-2 segregation in multiple family members.

We present a family with multiple carriers of a subtle balanced translocation t(14;21)(q21.2;q21.2) and three patients with a resultant adjacent-2 malsegregation containing a +der(14)t(14;21)(q21.

Case report: two patients with oculocerebrocutaneous syndrome and terminal digital amputations.

We report 2 cases of patients with a rare multiple anomaly condition reported as Dellman (oculocerebrocutaneous) syndrome. In this article we discuss the clinical features and genetics of this condition. Notably, both of these patients have digital abnormalities which have not been previously described in the literature.

Array-based comparative genomic hybridization analysis of 1176 consecutive clinical genetics investigations.

Purpose: Cytogenetic investigations are useful for etiologic determinations of mental retardation, developmental delay, multiple congenital anomalies, and pregnancy complications; however, the causes remain elusive in a majority of cases despite high-resolution cytogenetic studies and multiple fluorescence in situ hybridization examinations. Array-based comparative genomic hybridization has the ability to examine the genome at a higher resolution and may yield an increased detection of genetic abnormalities. The purpose of this study was to assess the use of array-based comparative genomic hybridization in a clinical genetics setting.

Macrocephaly syndromes.

Anatomic megalencephaly resulting in macrocephaly occurs in more than 100 multiple congenital anomaly syndromes. A number of macrocephaly syndromes show accompanying somatic overgrowth, but some show normal somatic growth. This discussion provides a review of several macrocephaly syndromes that might be encountered by the pediatric neurologist.

Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts.

We report a new fibroblast and lymphoblast based protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzymatic assay, which allows rapid and accurate diagnosis of carriers and patients with muscle-eye-brain type of congenital muscular dystrophy. Seven patients with genetically confirmed muscle-eye-brain disease were assayed for protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzyme activity. In three patients and their heterozygous parents, the assays were done on EBV-transformed lymphoblasts, in another three patients they were done on cultured fibroblasts and in the last patient on both fibroblasts and lymphoblasts.