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Apert syndrome was diagnosed in a newborn with typical facial and digital features whose only detected prenatal abnormality had been agenesis of the corpus callosum. This prompted a review of the central nervous system findings in all cases of Apert syndrome treated at the Craniofacial Center Boston Children's Hospital between 1978 and 2004. Two of 30 patients with Apert syndrome had prenatal identification of mild dilatation of the lateral cerebral ventricles and complete agenesis of the corpus callosum (ACC) documented with both ultrasound and MRI. Both had the common S252W mutation of FGFR2. Though cranial and orbital malformations typical of Apert were eventually seen in these fetuses in the third-trimester, even in retrospect, these were not detectable at mid second-trimester, ultrasound screening for congenital malformations. Hand malformations also went undetected in the second-trimester despite extensive imaging by experienced radiologists. We conclude that prenatal ultrasonographic identification of mild ventriculomegaly or ACC should stimulate a careful search for features of Apert syndrome and prompt follow-up imaging to look for bony abnormalities that have later onset. Prenatal molecular testing for Apert mutations should be considered in cases of mild ventriculomegaly and ACC.

Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5' UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784-789]. On the other hand, the 5q translocation breakpoint disrupts the 3' UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3' UTR disruption as the cause of the proband's LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3' portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.

Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the “extended OTCD phenotype”. We present a male with neonatal-lethal OTCD due to a 1.87 Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings.

Importance Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. Objective To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. Design, Setting, and Participants We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. Main Outcomes and Measures Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. Results We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. Conclusions and Relevance This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

The differential diagnosis of exophthalmos requires careful examination to identify potentially serious aetiologies. We present the case of a child with exophthalmos in whom genetic analysis identified a mutation in the fibroblast growth factor receptor 2 associated with Crouzon syndrome. The variable presentation should remind paediatricians to consider mutations in fibroblast growth factor receptor 2 among the aetiologies of exophthalmos.

Apparently balanced chromosomal rearrangements in individuals with major congenital anomalies represent natural experiments of gene disruption and dysregulation. These individuals can be studied to identify novel genes critical in human development and to annotate further the function of known genes. Identification and characterization of these genes is the goal of the Developmental Genome Anatomy Project (DGAP). DGAP is a multidisciplinary effort that leverages the recent advances resulting from the Human Genome Project to increase our understanding of birth defects and the process of human development. Clinically significant phenotypes of individuals enrolled in DGAP are varied and, in most cases, involve multiple organ systems. Study of these individuals' chromosomal rearrangements has resulted in the mapping of 77 breakpoints from 40 chromosomal rearrangements by FISH with BACs and fosmids, array CGH, Southern-blot hybridization, MLPA, RT-PCR, and suppression PCR. Eighteen chromosomal breakpoints have been cloned and sequenced. Unsuspected genomic imbalances and cryptic rearrangements were detected, but less frequently than has been reported previously. Chromosomal rearrangements, both balanced and unbalanced, in individuals with multiple congenital anomalies continue to be a valuable resource for gene discovery and annotation.

Fabiola Quintero-Rivera, Natalia T. Leach, Albert de la Chapelle, James F. Gusella, Cynthia C. Morton, and David J. Harris* Massachusetts General Hospital, Center for Human Genetic Research, Boston, Massachusetts Brigham and Women’s Hospital, Departments of Obstetrics, Gynecology, Reproductive Biology and Pathology, Boston, Massachusetts Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts The David Geffen School of Medicine at UCLA, Department of Pathology, Los Angeles, California

BackgroundWiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation.Case presentationFor patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3-4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively.ConclusionsBased on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.

Pierre Robin sequence (PRS) is a malformation pattern characterized by the core triad of retrognathia, glossoptosis, and cleft palate that causes difficulty in glossopharyngeal-laryngeal-vagal functions. The etiology of PRS remains largely unknown; previous reports have suggested that it is caused by intrauterine constriction or external conditions such as oligohydramnios, breech position, or abnormal uterine anatomy. Genetic causes include occurrence as a manifestation of many single gene conditions and chromosomal rearrangements. Positional effect on some loci or genes, including SOX9 has also been posited as a cause. Here, we report on an 18-month-old girl born with isolated PRS. Clinical chromosome microarray analysis (CMA) revealed a maternally inherited ~623 kb microdeletion that is -725 kb upstream of 5' SOX9 at chromosome locus 17q24.3. Her mother had cleft palate. This region, although devoid of any genes, is known to have a position effect on SOX9 due to elimination of highly conserved non-coding cis-regulatory elements. This report supports the evidence that deregulation of an intact SOX9 coding region is a cause of or associated with isolated PRS, and provides further evidence that CMA in the clinical setting is a powerful tool in detecting microdeletions in gene "desert" regions that have pathogenic position effect on specific genes.

Cat-Eye syndrome (CES), (OMIM 115470) also known as chromosome 22 partial tetrasomy or inverted duplicated 22q11, was first reported by Haab [1879] based on the primary features of eye coloboma and anal atresia. However, >60% of the patients lack these primary features. Here, we present a 9-month-old female who at birth was noted to have multiple defects, including facial asymmetry with asymmetric retrognathia, bilateral mandibular hypoplasia, branchial cleft sinus, right-sided muscular torticollis, esotropia, and an atretic right ear canal with low-to-moderate sensorineural hearing loss, bilateral preauricular ear tag/pits, and two skin tags on her left cheek. There were no signs of any colobomas or anal atresia. Hemifacial microsomia (HFM) was suspected clinically. Chromosome studies and FISH identified an extra marker originated from 22q11 consistent with CES, and this was confirmed by aCGH. This report expands the phenotypic variability of CES and includes partial tetrasomy of 22q11.1-q11.21 in the differential diagnosis of HFM. In addition, our case as well as the previous association of 22q11.2 deletions and duplications with facial asymmetry and features of HFM, supports the hypothesis that this chromosome region harbors genes important in the regulation of body plan symmetry, and in particular facial harmony.

We report here a child with a ring chromosome 2 [r(2)] associated with failure to thrive, microcephaly and dysmorphic features. The chromosomal aberration was defined by chromosome microarray analysis, revealing two small deletions of 2p25.3 (139 kb) and 2q37.3 (147 kb). We show the clinical phenotype of the patient, using a conventional approach and the molecular cytogenetics of a male with a history of prenatal intrauterine growth restriction (IUGR), failure to thrive, microcephaly and dysmorphic facial features. The phenotype is very similar to that reported in other clinical cases with ring chromosome 2.

We report on a 3½-year-old African American female with a 1.63 Mb microdeletion in 5q35.2-q35.3. This deletion includes NSD1, the gene that causes Sotos syndrome. The patient has unilateral cleft lip and palate (CLP) status postrepair, an unrepaired alveolar cleft, speech delay, global developmental delay, macrocephaly, mild cerebral palsy, and a patent ductus arteriosus status postrepair. Dysmorphic features include a prominent forehead and midface hypoplasia. This is one of the first cases of CLP associated with Sotos syndrome and emphasizes the utility of chromosomal microarray analysis in patients with more than isolated CLP in the Craniofacial Clinic.

We present the case of an 18-month-old boy with dysmorphic facial features, developmental delay, growth retardation, bilateral clubfeet, thrombocytopenia, and strabismus, whose array CGH analysis revealed concurrentde novotrisomy 10p11.22p15.3 and monosomy 7p22.3. We describe the patient's clinical presentation, along with his cytogenetic analysis, and we compare the findings to those of similar case reports in the literature. We also perform a bioinformatic analysis in the chromosomal regions of segmental aneuploidy to find genes that could potentially explain the patient's phenotype.

The screening of individuals with mild dysmorphic features and mental retardation using whole genome scanning technologies has resulted in the delineation of several previously unrecognized microdeletion syndromes. Microdeletion of 3q29 has been recently described as one such new syndrome. The clinical phenotype is variable despite an almost identical submicroscopic deletion size in most cases. We report on two individuals that further expand the clinical presentation of this rare disorder and compare the findings with earlier reports to refine the 3q29 microdeletion syndrome phenotype. The propositi are a 10-year-old female and a 15-year-old male, who have in common intellectual disabilities, a history of autism and psychiatric symptoms ranging from bipolar disorder presenting with increasing suicidal ideation to aggressive behavior and general anxiety. Other shared physical findings include asymmetric face, high-nasal bridge, crowded/dysplastic teeth, and tapered fingers. Oligonucleotide array-based chromosomal microarray analysis (CMA) using a genome-wide SNP array identified a de novo subtelomeric microdeletion of chromosome region 3q29 ranging from 1.6 to 2.1 Mb. The region of overlap encompasses 20 RefSeq genes, including FBX045, DLG1, and PAK2. These genes are related to neuronal postsynaptic membrane function and PTEN signaling, suggesting a role for synaptic connectivity dysfunction in the etiology of autism in these children. The novel clinical presentation of our patients expands the clinical spectrum of the 3q29 microdeletion syndrome and provides additional insights into the pathophysiology of autism and psychiatric disorders.

Duplication 22q11.2 syndrome is the result of a microduplication of the same chromosomal region that is deleted in DiGeorge and Velocardiofacial syndromes. We describe a patient with dysmorphic features who was diagnosed with pre-B acute lymphoblastic leukemia, and developed cystinuria and pancreatitis during treatment. Duplication 22q11.2 has not been previously described in association with hematologic abnormalities. Chromosomal microarray technology was used to diagnose duplication 22q11.2 syndrome. In this era of advanced genomics, this technology has become an important method for helping to determine the molecular basis of diseases, best treatments and ultimately patient outcomes.

We describe the outcome of two consecutive pregnancies with a clinical presentation of ornithine transcarbamylase (OTC) deficiency (OTCD) without a molecular diagnosis. A 119kb deletion on Xp11.4 including the OTC gene was detected in the mother. The same deletion was identified in the blood spots from deceased male newborns. In patients with a clinical and biochemical presentation of OTCD and negative OTC sequencing, whole genome or targeted chromosomal microarray analysis (CMA) with coverage of the OTC and neighboring genes should be performed as a reflex test.

Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia−/− knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia +/− and Nfia −/− phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia +/− and Nfia −/− mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects., Author Summary Central nervous system (CNS) and urinary tract abnormalities are common human malformations, but their variability and genetic complexity make it difficult to identify the responsible genes. Analysis of human chromosomal abnormalities associated with such disorders offers one approach to this problem. In five individuals described herein, a novel human syndrome that involves both CNS and urinary tract defects is associated with chromosomal disruption or deletion of NFIA, encoding a member of the Nuclear Factor I (NFI) family of transcription factors. This syndrome includes brain abnormalities (abnormal corpus callosum, hydrocephalus, ventriculomegaly, and Chiari type I malformation), spinal abnormalities (tethered spinal cord), and urinary tract abnormalities (vesicoureteral reflux). Nfia disruption in mice was already known to cause hydrocephalus and abnormal corpus callosum, and is now shown to exhibit renal defects and disturbed ureteral development. Other genes besides NFIA are also disrupted or deleted and may contribute to the observed phenotype. However, loss of one copy of NFIA is the only genetic defect common to all five patients. The authors thus provide evidence that genetic loss of NFIA contributes to a distinct CNS malformation syndrome with urinary tract defects of variable penetrance.

Fabiola Quintero-Rivera, Caroline D. Robson, Rosemary E. Reiss, Deborah Levine, Carol B. Benson, John B. Mulliken, and Virginia E. Kimonis* Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts Department of Radiology, Children’s Hospital, Boston, Massachusetts Maternal Fetal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts Division of Plastic Surgery, Children’s Hospital, Boston, Massachusetts Division of Genetics and Metabolism, Children’s Hospital, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts

ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (