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BackgroundSeverity is an important factor for inclusion of diseases on expanded carrier screening (ECS) panels. Here, we applied a validated algorithm that objectively classifies diseases into severity categories to 176 genes on a clinically available ECS panel. We then mapped disease traits from the algorithm to severity-related criteria cited by the American College of Obstetricians and Gynecologists (ACOG).MethodsEight genetic counselors (GCs), followed by four medical geneticists (MDs), applied the algorithm to subsets of the 176 genes. MDs and GCs then determined which disease traits met ACOG severity criteria.ResultsUpon initial GC and MD review, 107/176 genes (61%) and 133/176 genes (76%), respectively, had concordant classifications, with consensus reached for all genes. Final severity classifications were 68 (39%) profound, 71 (40%) severe, 36 (20%) moderate, and one (1%) mild. The vast majority of genes (170 out of 176) met at least one of ACOG’s four severity criteria.ConclusionThis study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of an algorithm. Further, it clarified and operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation across laboratories.What’s already known about this topic?Disease severity is an important consideration for disease inclusion on expanded carrier screening panels.An algorithm that objectively classifies diseases into severity categories has been published and validated.What does this study add?176 genes were classified into severity categories.The algorithm was used to bring clarity to American College of Obstetricians and Gynecologist’s (ACOG’s) severity criteria that are not easily interpretable.170 of 176 genes met at least one of ACOG’s severity criteria.Data Availability StatementThe data that support the findings of this study have been completely reported in this manuscript and shared in the Figures and Supplementary Material.

BackgroundRare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.MethodsClinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.ResultsClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).ConclusionsVariants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes.Clinical and molecular characterisation was performed on 17 patients withClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygousVariants in

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Advances in genetic testing have led to the identification of increasing numbers of novel gene mutations that underlie infantile-onset epileptic encephalopathies. Recently, a mutagenesis screen identified a novel gene, SZT2, with no known protein function that has been linked to epileptogenesis in mice. Thus far, two clinical reports have identified children with different recessive mutations in SZT2 and varying clinical phenotypes. One case report described patients with epileptic encephalopathy and the other noted patients with cognitive deficiencies, but normal MRI and no epilepsy. This case report identifies novel mutations (a compound heterozygous frameshift and a nonsense variant) in the SZT2 gene with distinct clinical and radiographic findings relative to those previously reported. Our patient presented with intractable epilepsy at 2 months of age. Seizures were refractory to numerous antiepileptic medications and the patient finally achieved seizure cessation at age 3 years with a combination of divalproex and lamotrigine. Our patient had similar facial dysmorphisms (macrocephaly, high forehead, and down-slanted palpebral fissures) to a previous case with truncating mutation. While developmental delay and cognitive deficiencies were present, our case had unique MRI findings suggesting migrational abnormalities not previously reported in other cases.

Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc.

Exome sequencing is an effective way to identify genetic causes of etiologically heterogeneous conditions such as developmental delay and intellectual disabilities. Using exome sequencing, we have identified four patients with similar phenotypes of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects who all have the same de novo R331W missense variant in C-terminal binding protein 1 (CTBP1). CTBP1 is a transcriptional regulator critical for development by coordinating different regulatory pathways. The R331W variant found in these patients is within the C-terminal portion of the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft, which is the domain through which CTBP1, interacts with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. This is the first report of mutations within CTBP1 in association with any human disease.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Chromosomal microdeletion syndromes are frequently associated with neurological disease including epilepsy and behavioral abnormalities. Yet, for most microdeletions, neurological phenotypes are variable and the exact molecular cause of neurological disease is not yet understood. Terminal deletions in the long arm of chromosome 2 (2q37.3) are among the most common microdeletion syndromes diagnosed, and have been associated with epilepsy, autistic-like features, short stature, obesity, and brachydactyly type E (short 4th and 5th metacarpals and metatarsals). However, neither epilepsy nor any of the other clinical features are invariant in 2q37.3 deletion. To elucidate the genetic mechanisms underlying this clinical variability we report what is, to our knowledge, the first description of inherited 2q37.3 deletion (without other complex chromosomal rearrangements) in three family members and present two sporadic cases and accompanying chromosomal microarray data. The clinical features of the three familial and two sporadic cases combined with the chromosomal microarray results suggest that all of the clinical features seen in 2q37.3 deletion may be variably expressed.

Neurologic regression in a previously healthy child may be caused by metabolic or neurodegenerative disorders, many of which have no definitive treatment. We report a case of a previously healthy 8-year-old boy who presented with a month-long history of waxing and waning encephalopathy and acute regression, followed by seizures. Evaluation for a metabolic disorder revealed methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C type due to a single, presumed homozygous pathogenic c.394 C>T mutation in the MMACHC gene. With the appropriate diet restrictions and vitamin replacement, he improved significantly and returned to his premorbid level of behavior. This case illustrates an unusual presentation of a treatable metabolic disorder and highlights the need to consider cobalamin defects in the differential diagnosis of healthy children with neurologic regression.

Ayme-Gripp syndrome (AGS) is an autosomal dominant multisystem disorder caused by specific heterozygous variants in MAF. The resulting aberrant protein shows impaired GSK-mediated MAF phosphorylation. AGS is characterized by congenital cataracts, sensorineural hearing loss, short stature, intellectual disability, and distinctive facial features with brachycephaly. Cardiac and joint phenotypes are present in nearly half of patients. We review information on 10 published individuals with MAF mutations and clinical AGS and describe five additional patients, including three with novel mutations. Joint problems, typically including radioulnar synostosis and joint limitations, were present in 9/15 patients. Hip replacement in young adulthood was needed in four patients. Pericarditis occurred in 6/15 individuals. An automated facial analysis of 2D photos was used to compare the facial phenotype of 13 individuals from the literature or reported here, with facial photos of a control cohort of unaffected individuals and a cohort of Down syndrome patients. A multiclass approach yielded an accuracy of 86.86% and 89.05%, respectively, in two independent experiments compared to a random chance of 37.74%. In binary comparisons of AGS and Down syndrome, the area under the curve (AUC) was 0.994 (P < .001) and 1.0 (P < .001), respectively. Binary comparisons of AGS and unaffected controls yielded AUC of 0.994 (P < .001) and 0.989 (P = .003), respectively, suggesting that the facial phenotype of AGS could clearly be distinguished from unaffected individuals and from Down syndrome patients. Automated facial analysis may be helpful in the identification and evaluation of individuals suspected to have AGS.

To evaluate the growth, development, and medical histories of children with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening.Chart review of patients diagnosed with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiency at our center.There were 16 children with short-chain acyl-CoA dehydrogenase deficiency, including 10 with two pathogenic mutations, and 8 with isobutyryl-CoA dehydrogenase deficiency. All but one patient has had normal growth and development, and that patient also had the 22q deletion syndrome.Our data and previous reports suggest that the majority of individuals with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiencies have normal growth and development.

Microduplications of the Sotos syndrome region containing NSD1 on 5q35 have recently been proposed to cause a syndrome of microcephaly, short stature and developmental delay. To further characterize this emerging syndrome, we report the clinical details of 12 individuals from 8 families found to have interstitial duplications involving NSD1, ranging in size from 370 kb to 3.7 Mb. All individuals are microcephalic, and height and childhood weight range from below average to severely restricted. Mild-to-moderate learning disabilities and/or developmental delay are present in all individuals, including carrier family members of probands; dysmorphic features and digital anomalies are present in a majority. Craniosynostosis is present in the individual with the largest duplication, though the duplication does not include MSX2, mutations of which can cause craniosynostosis, on 5q35.2. A comparison of the smallest duplication in our cohort that includes the entire NSD1 gene to the individual with the largest duplication that only partially overlaps NSD1 suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the abnormal growth parameters seen in these patients. NSD1 duplications may therefore be added to a growing list of copy number variations for which deletion and duplication of specific genes have contrasting effects on body development.

Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis–trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis–trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis–trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.

BACKGROUND De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging. METHODS We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist. RESULTS Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions. CONCLUSIONS This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.

Glutaric acidemia type II (GAII) is an inborn error of metabolism caused by defects in electron transport flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO) and typically presents with hypo- or nonketotic hypoglycemia and metabolic acidosis. The most severe forms present in early infancy and are associated with a high mortality rate. The disorder can now be detected by expanded newborn screening using tandem mass spectrometry (MS/MS), providing the opportunity for diagnosis and treatment in asymptomatic infants. We report here three infants who, despite diagnosis and treatment in the neonatal period, experienced either unexpected sudden death or an acute life-threatening event (ALTE) during the first year of life. The possible etiologies of these events and the potential impact of expanded newborn screening on the long-term outcome of GAII are discussed.

Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase–deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase– and short-chain acyl-CoA dehydrogenase–deficient patients. Results: Quantification of C4-acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase–deficient from short-chain acyl-CoA dehydrogenase–deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase–deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C4-acylcarnitine identified through newborn screening.

Partial duplication of chromosome 3q is a well-described condition of multiple congenital anomalies and developmental delay that resembles the Brachmann-de Lange syndrome. Similarly, an emerging phenotype of a distal 5q deletion syndrome has recently been described. The combination of both chromosome abnormalities has not been previously described. We report on a child with both a de novo duplication of distal 3q (q27 --> qter) and terminal deletion of 5q (q35.2 --> qter). The patient had facial anomalies, hypoplastic toenails, lymphedema of the dorsum of the feet, type I Chiari malformation, a seizure disorder, and moderate developmental delays. The phenotype is compared and contrasted to the few reports of patients with similar terminal 3q duplications and 5q deletions. Our patient did not have the characteristic phenotype of the 3q duplication syndrome, suggesting that the chromosome region responsible for this phenotype is more proximal than the terminal 3q27 region. In addition, comparison with three other reported cases of terminal 5q35 deletions suggests a possible association of terminal 5q deletions with central nervous system (CNS) structural abnormalities.

We report on monozygotic (MZ) twins with a de novo chromosome abnormality consisting of a partial duplication of chromosome 4 (q25-qter) and deletion of chromosome 1p36. These infants had dysmorphic facial features and other clinical manifestations similar to those described with the previously delineated duplication 4q and deletion 1p36 phenotypes and two other reported cases of combined partial duplication 4q and deletion 1p36. However, the twins were discordant for a number of congenital anomalies. The discordant phenotypes described in these genetically identical infants demonstrate that nongenetic factors may play a significant role in the phenotypic differences in patients with recognized chromosome duplication and deletion syndromes, which are usually attributed to the individual genotypic differences in the duplicated and/or deleted chromosome segments. © 2002 Wiley-Liss, Inc.

We report on two patients with an unusual combination of multiple congenital anomalies including holoprosencephaly, encephalocele, and additional defects commonly observed in the VACTERL and schisis “associations.” One of the infants had a chromosome abnormality characterized by partial duplication and deletion of chromosome 18. VACTERL association was characterized recently as a primary developmental field defect (DFD) [Martinez-Frias et al., 1998: Am J Med Genet 76:291–296]. In some cases, sequences may also represent uncomplicated DFDs. We suggest that findings in both of these cases represent abnormalities of blastogenesis involving the primary field resulting in holoprosencephaly and VACTERL and schisis anomalies, and show that similar primary DFDs are causally heterogeneous. © 2002 Wiley-Liss, Inc.

Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the first study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.

We report on a male infant with partial trisomy 2q (q34-->qter) resulting from a maternal pericentric inversion of chromosome 2 (p25. 2q34). The infant had clinical findings similar to the characteristic phenotype associated with a partial duplication of chromosome 2q3. Carriers of pericentric inversions of chromosome 2 have an increased risk of pregnancy loss but have only rarely been reported to have a liveborn offspring with an unbalanced chromosome constitution. This case further confirms the risks associated with a pericentric inversion of chromosome 2 and is the second report with manifestations of the trisomy 2q3 phenotype.

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

We report on a female infant with partial trisomy 9p (pter-->p13) and partial trisomy 14q (pter-->q22) resulting from a 3:1 segregation of a maternal reciprocal translocation (9;14)(p13;q22). Both trisomy 9p and partial trisomy 14q have been described as recognized phenotypes with characteristic patterns of anomalies. This patient appears to be the first reported with a partial duplication of both 9p and 14q resulting in an overlapping phenotype including minor facial anomalies, cleft palate, and hand-foot anomalies. However, the facial findings were more pronounced than commonly observed in cases with only one or the other duplicated chromosome regions, resulting in a distinctive appearance.

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk.

BACKGROUND: Certain ultrasonographic findings identified in a fetus suspected of having a skeletal dysplasia may be predictive of a lethal outcome. METHODS: We evaluated 27 fetuses suspected of having a skeletal dysplasia using targeted ultrasonography between 16 and 31 weeks' gestation. Clinical examination and skeletal radiography were done after delivery. RESULTS: A skeletal dysplasia was confirmed and a diagnosis established in all but one case. The skeletal dysplasia was lethal in 23 cases and, in each case, the outcome was accurately predicted prenatally; however, three of the infants survived several months. In 11 of the 23 cases (48%), the specific diagnosis was correctly determined before birth. Ultrasonographic findings not considered to reflect a lethal outcome, were accurately predicted in two other cases. In an additional two, sonographic examination suggested a lethal osteochondrodysplasia, though both survived. Findings consistent with a lethal skeletal dysplasia included a femur length < 1st centile, combined with either a bell-shaped thorax, decreased bone echogenicity, or both. Using these criteria provided a positive-predictive value for neonatal deaths of 80% (20/25), and 92% (23/25) if the three that died in infancy were included. CONCLUSIONS: In the fetus suspected of having a skeletal dysplasia, certain findings on targeted ultrasonography frequently are predictive of a lethal outcome; the ability to predict this appears greatest when more than one of these abnormalities is present.

We report on a female with lymphedema, facial anomalies, intestinal lymphangiectasia, and moderate mental retardation consistent with the diagnosis of Hennekam syndrome. In addition, she had a number of other anomalies not previously described in this autosomal recessive disorder, including a congenital heart defect, atretic ear canals, vesicoureteral reflux, and rectal prolapse.

Most phenotypic females with an XY male karyotype do not have significant extragenital anomalies; however, some patients with additional abnormalities have been described. We report on an individual with XY gonadal dysgenesis, mental retardation, microcephaly, growth retardation, and multiple pterygia. Although not previously reported, the possible relationship between these findings is discussed in the context of evident heterogeneity of XY gonadal dysgenesis.

We report on a patient with multiple congenital anomalies including anophthalmia, cleft lip and palate, and central nervous system anomalies similar to the case reported by Leichtman et al. [1994: Am J Med Genet 50:39-41] and to oculocerebrocutaneous (Delleman) syndrome. Although the two cases and those with oculocerebrocutaneous syndrome may represent separate but overlapping entities, our patient and the case described by Leichtman et al. [1994: Am J Med Genet 50:39-41] may represent a more severe form of oculocerebrocutaneous syndrome.

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, L-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of t-ornithine and/or an arginine-restricted diet (250 mg/kg/d L-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein β3 (GNB3). We generated a transgenic mouse model that carries an extra copy of GNB3, weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.

The incidence of haemangiomas was ascertained by questionnaire in infants born to 578 consecutive CVS patients and 445 consecutive mid-trimester amniocentesis patients seen at a single institution between 1 January 1989 and 31 May 1991. The incidence of 7.4 per cent reported in the amniocentesis group was comparable to previous estimates of the incidence of haemangiomas in the general population. In contrast, a 21.1 per cent incidence, three-fold higher than that observed in the amniocentesis group, was observed among CVS-exposed infants (P < 0.001). This increased incidence was largely confined to patients undergoing a transcervical procedure. No correlation was observed between the incidence of haemangiomas and gestational age at sampling, sample size, number of sampling attempts, or a history of bleeding following the procedure.

Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02).Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.

In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information. © 1994 Wiley-Liss, Inc.

We report on a case of cloverleaf skull deformity in a patient with hypochondroplasia, a disorder which has not been previously associated with this anomaly. Hypochondroplasia is a bone dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Cloverleaf skull is a trilobar skull deformity which is etiologically and genetically heterogeneous and occurs in association with a number of disorders which result from mutations in the fibroblast growth factor receptor genes. Our patient demonstrated one of the common FGFR3 mutations identified in hypochondroplasia, a C-to-A change at nucleotide 1620 (C1620A) in the tyrosine kinase domain. The occurrence of a cloverleaf skull deformity appears to represent an example of variable expressivity in hypochondroplasia and suggests that additional factors other than a specific mutation can modify the phenotype in this disorder. In addition, identification of another FGFR mutation associated with cloverleaf skull further illustrates the genetic heterogeneity of this anomaly.

A 23-year-old black man was admitted to hospital with infected leg ulcers. He had had ulcers since he was age 15, and had been admitted to hospital for infections on many occasions. Three previous skin grafts had failed. He had no history of diabetes or other illnesses. Haemoglobin electrophoresis had excluded sickle-cell disease and thalassaemias. Serological testing was negative for vascular collagen disease, and autoimmune disorders. There was no history of deep-vein thrombosis and previous arteriography, venograms, and Doppler ultrasound studies were normal. He had a 2 3 cm ulcer over his left medial malleolus and a 3 4 ulceration over his left anterior tibia. Family history was remarkable for five maternal male relatives who had chronic leg ulcers with onset ranging from their mid-teen years to early twenties (figure). Leg ulcerations affect approximately 1% of the population, 40–80% are caused by post-thrombotic disease. Genetic disorders of coagulation have been identified as causing familial venous thrombosis including mutations in protein C, protein S, antithrombin III, fibrinogen, and factor V genes. There was no evidence of a coagulopathy in this patient and no history of venous thrombotic events in any of the affected individuals. Leg ulcers also occur in individuals with prolidase deficiency, a rare autosomal recessive metabolic disorder associated with abnormal facial characteristics, mental retardation, and splenomegaly, which was not the case here.

Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. We identified a patient with recessive inheritance of a missense mutation (169G--A; E57K) in the Fibulin-4 gene. She had multiple bone fractures at birth and was diagnosed with cutis laxa, vascular tortuosity, ascending aortic aneurysm, developmental emphysema, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum by age 2 years. Her skin showed markedly underdeveloped elastic fibers, and the extracellular matrix laid down by her skin fibroblasts contained dramatically reduced amounts of fibulin-4. We conclude that fibulin-4 is necessary for elastic fiber formation and connective tissue development.