Search

The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with intellectual disability ( ID). First, 10 experienced clinicians (five from Africa and five from Europe) rated gestalt in 127 African non-Down Syndrome (non- DS) patients using either the score 2 for 'clearly dysmorphic', 0 for 'clearly non dysmorphic' or 1 for 'uncertain'. The inter-rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters ( kappa-coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome ( DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80%) compared to African (36.8%). We trained the Face2Gene with a set of African DS and non- DS photographs. Interestingly, the recognition in African increased to 94.7%. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing ( NIPT) for fetal aneuploidy detection is increasingly being offered in the clinical setting. Whereas the majority of tests only report fetal trisomies 21, 18 and 13, genome-wide analyses have the potential to detect other fetal, as well as maternal, aneuploidies. In this review, we discuss the technical and clinical advantages and challenges associated with genome-wide cell-free fetal DNA profiling. [ABSTRACT FROM AUTHOR]

Children with unexplained developmental disabilities or congenital anomalies are increasingly being referred for genetic diagnostic testing using array-comparative genomic hybridisation (array- CGH) and next-generation sequencing ( NGS) technologies. Their parents will have to deal with the secondary variants that will inevitably arise. We conducted 16 prospective semi-structured interviews with native Dutch-speaking parents whose children had undergone clinical array- CGH testing. The interviews explored the parents' experiences, expectations and opinions, specifically regarding the communication of results. Concrete examples of 'unexpected results' were provided to help guide the discussion, differing in severity, treatability, time of onset, level of risk, and carrier status. Data was analysed using content and narrative analysis methodologies. Parental motivations for and against the disclosure of unexpected results cluster around four main themes: actionability; knowledge; context; and characteristics of the result. Most parents wished to know all types of results. Disclosure was framed within a holistic, contextual, family-wide view. Genetic counselling should aim to integrate explorations of the motivations of parents surrounding the disclosure of results with good clinical care. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. Methods We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. Results The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. Conclusions Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations. © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which reports the duplication or mutation in the faciogenital dysplasia 1 (FGD1) gene in Aarskog-Scott syndrome.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is a congenital birth defect affecting around 1/3000 births. We propose that a significant number of isolated CDH cases have an underlying genetic cause, and that a subset of these result from copy number variations (CNVs) identifiable by array CGH. METHODOLOGY: We have designed a custom array targeted at genes and genomic loci associated with CDH. A total of 79 isolated CDH patients were screened using this targeted array. RESULTS: In three patients, we detected genomic imbalances associated with the observed diaphragmatic hernia; a deletion of 8p22-p23.3, 14.2 Mb in size, a 340 kb duplication of Xq13.1 including the ephrin-B1 gene (EFNB1), and mosaicism for trisomy 2. CONCLUSION: Using this approach, we detected genomic imbalances associated with CDH in 3/79 (4%) isolated CDH patients. Our findings further implicate 8p deletions as being associated with CDH. The duplication of EFNB1 further highlights this gene as a potential candidate involved in diaphragm development. Mosaicism for trisomy 2 is a rare event and unlikely to be a common cause of CDH. Further investigations of isolated CDH patients by array CGH will continue to identify novel submicroscopic loci and refine genomic regions associated with CDH. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Crepel A, Breckpot J, Fryns J-P, De la Marche W, Steyaert J, Devriendt K, Peeters H. DISC1 duplication in two brothers with autism and mild mental retardation. We describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family. [ABSTRACT FROM AUTHOR]

Focal dermal hypoplasia (FDH), Goltz or Goltz–Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes. [ABSTRACT FROM AUTHOR]

Structured Abstract Authors – Swinnen S, Bailleul-Forestier I, Arte S, Nieminen P, Devriendt K, Carels C Objectives – To describe the dentofacial phenotypes of three sisters with severe non-syndromic oligodontia, to report on the mutation analysis in three genes, previously shown to cause various phenotypes of non-syndromic oligodontia and in two other suspected genes. Based on the phenotypes in the pedigree of this family, the different possible patterns of transmission are discussed. Methods – Anamnestic data and a panoramic radiograph were taken to study the phenotype of the three sisters and their first-degree relatives. Blood samples were also taken to obtain their karyotypes and DNA samples. Mutational screening was performed for the MSX1, PAX9, AXIN2, DLX1 and DLX2 genes. Results – The probands’ pedigree showed evidence for a recessive or multifactorial inheritance pattern. Normal chromosomal karyotypes were found and – despite the severe oligodontia present in all three sisters – no mutation appeared to be present in the five genes studied so far in these patients. Conclusions – In the three sisters reported, their common oligodontia phenotype is not caused by mutations in the coding regions of MSX1, PAX9, AXIN2, DLX1 or DLX2 genes, but genetic factors most probably play a role as all three sisters were affected. Environmental and epigenetic factors as well as genes regulating odontogenesis need further in vivo and in vitro investigation to explain the phenotypic heterogeneity and to increase our understanding of the odontogenic processes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Learning disabilities are one of the most consistently reported features in Velo-Cardio-Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS. In addition, we aimed to identify factors that may contribute to within-syndrome variability in cognitive performance, such as the mode of inheritance of the deletion, sex, the presence of a heart defect and psychiatric morbidity. METHOD: IQ data of 103 children with VCFS (56 males, 47 females) were collected. Psychiatric diagnosis was additionally recorded. RESULTS: Children with VCFS had a mean full-scale IQ (FSIQ) of 73.48 (range: 50-109). There were no effects of sex, presence of a heart defect and psychiatric condition on intellectual profile. Inheritance of the deletion affected cognitive performance in VCFS, with children with familial deletions having significant lower FSIQ than children with a de novo deletion. CONCLUSIONS: Learning disabilities are very common in children with VCFS, although marked within syndrome variability is noted. One factor contributing to this variability seems to be the mode of inheritance of the deletion. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the motor development of primary school children (age 5-14y) with a 22q11 deletion (del22q11) group and a control group. The effects of a congenital heart defect (CHD) and IQ on motor development were additionally studied within the del22q11 group. Motor development of 37 children with a del22q11 (20 males, 17 females; mean age 9y 4mo, range 5y 9mo-13y 3mo) and 34 controls (23 males, 11 females; mean age 9y 1mo, range 4y 8mo-13y 6mo) was assessed with the Bruininks-Oseretsky Test of Motor Proficiency. The del22q11 group showed a significant deficit in motor functioning compared with the control group (p < 0.01). Within the del22q11 group there was a significant effect of IQ on motor performance, but no effect of CHD was found. To conclude, primary school children with a del22q11 syndrome showed a significant deficit in motor performance compared with a control group. A significant effect of IQ on motor performance in del22q11 was found. [ABSTRACT FROM AUTHOR]

Segmental duplications or low-copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT-rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low-copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non-AT-rich NF1 -like region of low-copy repeat B (LCR-B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR-B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X. [ABSTRACT FROM AUTHOR]

Describes a family with autosomal dominant isolated velopharyngeal incompetence, a velopgharyngeal disorder. Manifestations of the disease; Hypernasal speech of the patients; Role of soft palate in the velopharyngeal insufficiency.

Presents a letter to the editor on the causal role of the Aristaless-related homeobox gene in the origin of the encephalocele and endocrine defects in a patient.

Ring chromosome 7 is an unusual chromosome anomaly. Here we describe a patient with ring chromosome 7 and we show that both subtelomeres are still present. The diagnosis agrees with ‘ring syndrome’. This report helps to further delineate the clinical manifestations of ‘ring syndrome’ and to distinguish the phenotypic consequences of the presence of a ring chromosome 7 from the phenotypic consequences of terminal chromosome 7 submicroscopic deletions. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a case of left isomerism with fetal heart abnormalities.

An abstract of the conference paper "Flow of patients with isolated congenital diaphragmatic hernia following referral to a fetal surgery unit" by E. Done and colleagues is presented.

An abstract of the conference paper "Skeletal dysplasias: does first trimester NT measurement matter?" by N. Roggen and colleagues is presented.

The evaluation of dysmorphism is often subjective because many continuous traits are not easily measured or lack normal values. Because many common morphologic profiles vary between populations, population-specific reference ranges of relevant traits are needed. We aim to evaluate the objective assessment of facial dysmorphism in 553 Congolese newborns based on facial measurements. Measurements taken with a ruler were on average larger compared to those with a caliper, but the bias did not depend on the size of the measurement. We therefore introduced a correction factor that allows to use both techniques for facial measurements interchangeably in future studies. The outer canthal distance, palpebral fissure length, and mouth width were significantly larger in Congolese newborns (respectively mean 6.59 [SD 0.48]; mean 2.20 [SD 0.24]; mean 2.78 [SD 0.26]) when compared to references based on European newborns (respectively mean 3.59 [SD 1.76]; mean 4.20 [SD 2.26]; mean 0.47 [SD 1.21]), while the rest of measurements were significantly smaller. The interpupillary distance (IPD) calculated from inner canthal distance and outer canthal distance was not significantly different. We observed a poor agreement between clinical evaluation and measured features (kappa of 0.432). Clinicians were more likely to recognize a face as having wide-spaced eyes when it had been recognized as such during the clinical examination, more than if the child had a high interpupillary distance. This suggests that the measured IPD is not precisely reflecting what is clinically evaluated as wide-spaced eyes., (© 2022 Wiley Periodicals LLC.)

Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable. The phenotype and evolution in a Congolese boy with XGS have been reported. At 6 years he had speech delay, drooling, marked hyperactivity, attention deficit, aggressive behavior, and intellectual disability. Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, uplifted ear lobes, flat philtrum, thin upper lip vermillion, high arched palate, and flat feet. Patient-only whole exome sequencing identified a known pathogenic frameshift variant in the AHDC1 gene [NM&#95;001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3)]. The clinical follow-up revealed the deterioration of his fine motor skills and significant cerebellar phenotype including tremor, pes cavus, and gait instability at the age of 12 years. This patient was compared with three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age., (© 2020 Wiley Periodicals LLC.)

In Central-Africa, neonatal infections, asphyxia and prematurity are main reasons for admission to the neonatal intensive care unit and major determinants of newborn survival. Also, the outcome of newborns with congenital anomalies is expected to be poor, due to a lack of state-of-the art care. We conducted a study of 102 newborns recruited in the Neonatal Intensive Care Unit (NICU) at the University Hospitals of Kinshasa, DR Congo, to assess the impact of congenital anomalies. The presence of a major anomaly was associated with a hazard ratio of death of 13.2 (95%CI: 3.7-46.7, p < .001). In addition, the presence of three or more minor anomalies was associated with a 4.5-fold increased risk of death (95%CI: 1.1-18.6, p = .04). We conclude that like major anomalies, the presence of three or more minor anomalies should also be given particular attention and that the evaluation of dysmorphism should be promoted in NICU., (© 2020 Wiley Periodicals LLC.)

The evaluation of minor physical variation is crucial in a dysmorphological examination. Currently, data on the spectrum and incidence of minor physical variants in Central African newborns is lacking. We therefore conducted a cross-sectional descriptive study of 722 newborns recruited within the first 24 hr of life, in two large maternities in Kinshasa, DR Congo. Minor anomalies were defined according to the series of articles in AJMG Part A and coded as human phenotype ontology terms. A total of 97 different morphological variants were recorded of which 13 were common. About 34.8% of the newborn carried one minor anomaly, 11.6% had two, and 4.3% had three minor anomalies. No gender differences were observed, but the incidence of specific anomalies appeared to vary with the geographical origin of parents within the DR Congo. The results of this study will aid clinicians to interpret morphological variation in Central African newborns., (© 2020 Wiley Periodicals, Inc.)

The 22q11.2 deletion syndrome (22q11.2DS) is the second most common cause of developmental delay after Down syndrome. Impaired cognitive development is highly prevalent, but also motor abnormalities such as hypotonia and delays in achieving motor milestones are described. Instability is frequently detected in children, adolescents, and adults and is mostly attributed to their limited motor performance. Until now, vestibular function has not been investigated in these patients, despite the growing evidence that they often have inner ear malformations. The aim of this prospective study was to identify the presence and character of vestibular dysfunction in 22q11.2DS. We investigated 23 subjects with proven 22q11.2DS, older than the age of 12. We performed caloric testing and pendular rotation chair tests with videonystagmography, cervical vestibular-evoked myogenic potential (c-VEMP)-testing, and posturography. Additional otoscopy and audiometry were performed on all subjects. We found a unilateral caloric hypofunction in 55% of patients, a certain absent c-VEMP response in 15% of ears, an inconclusive c-VEMP response in 33% of ears, and abnormal posturography in 68% of patients, of whom 42% displayed a typical vestibular pattern. Remarkably, 90% revealed uni- or bilateral weak caloric responses, independent of caloric symmetry. Vestibular dysfunction is frequent in subjects with 22q11.2DS. This knowledge should be taken into account when assessing motor performance in these patients. Additional larger studies are needed to determine whether this dysfunction implicates a therapeutic potential., (© 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Nonsyndromic orofacial clefting is one of the most frequently occurring congenital conditions. The aim of the study was to investigate the prevalence and nature of reduced olfactory function in patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P) and their unaffected first-degree relatives. Olfactory function was tested using the Sniffin' Sticks identification test in patients with NSCL/P, in their unaffected relatives, and in control subjects. MR imaging was performed to measure olfactory bulb (OB) volumes and olfactory sulcus (OS) depths. A reduced olfactory function was seen in significantly more patients with NSCL/P (p = .002) than in control subjects, regardless of the cleft type. Strikingly, unaffected relatives of patients with NSCL/P also had a higher rate of hyposmia (p = .001). In hyposmic patients, the OB volumes (left: p = .01 and right: p = .003) and the depth of the left OS (p = .02) were significantly smaller than in controls. In hyposmic relatives, both OS depths (left: p = .02 and right: p = .03) were significantly smaller. Patients with NSCL/P and their unaffected relatives have an increased prevalence of reduced olfactory function, associated with changes in the central olfactory structures., (© 2018 Wiley Periodicals, Inc.)

Pathogenic variants account for 4 to 41% of patients with intellectual disability (ID) or developmental delay (DD). In Sub-Saharan Africa, the prevalence of ID is thought to be higher, but data in Central Africa are limited to some case reports. In addition, clinical descriptions of some syndromes are not available for this population. This study aimed at providing an estimate for the fraction of ID/DD for which an underlying etiological genetic cause may be elucidated and provide insights into their clinical presentation in special institutions in a Central African country. A total of 127 patients (33 females and 94 males, mean age 10.03 ± 4.68 years), were recruited from six institutions across Kinshasa. A clinical diagnosis was achieved in 44 but molecular confirmation was achieved in 21 of the 22 patients with expected genetic defect (95% clinical sensitivity). Identified diseases included Down syndrome (15%), submicroscopic copy number variants (9%), aminoacylase deficiency (0.8%), Partington syndrome in one patient (0.8%) and his similarly affected brother, X-linked syndromic Mental Retardation type 33 (0.8%), and two conditions without clear underlying molecular genetic etiologies (Oculo-Auriculo-Vertebral and Amniotic Bands Sequence). We have shown that genetic etiologies, similar to those reported in Caucasian subjects, are a common etiologic cause of ID in African patients from Africa. We have confirmed the diagnostic utility of clinical characterization prior to genetic testing. Finally, our clinical descriptions provide insights into the presentation of these genetic diseases in African patients., (© 2018 Wiley Periodicals, Inc.)

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972&#95;973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome., (© 2018 Wiley Periodicals, Inc.)

Kabuki syndrome is a multiple congenital malformation syndrome with a spectrum of clinical features including short stature. Since there is no growth data on Kabuki syndrome patients with a proven KMT2D gene mutation, further research on growth and growth patterns is indicated. Data for this growth study on subjects with Kabuki syndrome were collected from referring clinicians. Subjects were eligible for inclusion in the study if the following criteria were met: a genetically confirmed diagnosis of Kabuki syndrome and no current treatment with growth hormones or other drugs that could influence growth. We present a report on growth data (n = 39) in Kabuki syndrome patients. The data showed that postnatal growth retardation is a clinical feature in all cases. All Kabuki syndrome subjects showed a growth deflection during childhood and a diminution of the pubertal growth spurt. A genotype-phenotype correlation was not observed. Further research is required in order to determine whether a defect in the growth hormone/IGF-I axis and estrogen receptor plays a role in the growth retardation. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The 22q11 deletion syndrome (22q11DS), the most frequent microdeletion syndrome in humans, presents with a large variety of abnormalities. A common abnormality is hearing impairment. The exact pathophysiological explanation of the observed hearing loss remains largely unknown. The aim of this study was to analyze the middle and inner ear malformations as seen on computer tomographic imaging in patients with 22q11DS. We retrospectively reviewed the charts of 11 22q11DS patients who had undergone a CT of the temporal bone in the past. Of the 22 examined ears, two showed an abnormal malleus and incus, 10 presented with a dense stapes superstructure, and three ears had an abnormal orientation of the stapes. With regard to the inner ear, 12 ears showed an incomplete partition type II with a normal vestibular aqueduct. In four ears the vestibule and lateral semicircular canal were composed of a single cavity, in 14 ears the vestibule was too wide, and three ears had a broadened lateral semicircular canal. These findings suggest that malformations of the stapes, cochlea, vestibule, and lateral semicircular canal are frequent in 22q11DS. To our knowledge, the current study involves the largest case series describing middle and inner ear malformations in 22q11DS. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases., (© 2016 Wiley Periodicals, Inc.)

Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known holoprosencephaly spectrum., (© 2015 Wiley Periodicals, Inc.)

To determine the diagnostic value of massive parallel sequencing of a panel of known cardiac genes in familial nonsyndromic congenital heart defects (CHD), targeted sequencing of the coding regions of 57 genes previously implicated in CHD was performed in 36 patients from 13 nonsyndromic CHD families with probable autosomal dominant inheritance. Following variant analysis and Sanger validation, we identified six potential disease causing variants in three genes (MYH6, NOTCH1, and TBX5), which may explain the defects in six families. Several problematic situations were encountered when performing genotype-phenotype correlations in the families to confirm the causality of these variants. In conclusion, by screening known CHD-associated genes in well-selected nonsyndromic CHD families and cautious variant interpretation, potential causative variants were identified in less than half of the families (6 out of 13; 46%). Variant interpretation remains a major challenge reflecting the complex genetic cause of CHD., (© 2015 Wiley Periodicals, Inc.)

MEIS2 has been associated with cleft palate and cardiac septal defects as well as varying degrees of intellectual disability. We present a female patient with a more severe phenotype compared to previous reported patients. She has multiple congenital malformations; cleft palate and congenital heart defect characterized by septal defects and aortic coarctation. She has severe feeding problems, facial dysmorphism, severely delayed gross motor and verbal development, and autism spectrum disorder. Facial dysmorphism consisting of bitemporal narrowing, arched and laterally extended eyebrows, mild upslanting palpebral fissures, deep-set eyes, a tented upper lip, thin upper vermilion, full lower vermilion, broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of toe II-III. Exome sequencing revealed a non-frameshift deletion (c.998&#95;1000del:p.Arg333del) of three base pairs in the MEIS2 homeodomain. The more severe phenotype is most probably due to dominant-negative mechanisms. This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development., (© 2015 Wiley Periodicals, Inc.)

Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5' untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C-terminus of FMRP. We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR1 locus. In one patient, we identified a guanine insertion in FMR1 exon 15. This mutation alters the open reading frame creating a short novel C-terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal (NLS) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C-terminus of FMRP. In vivo analyses in Drosophila demonstrate that a patient-mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials., (© 2015 Wiley Periodicals, Inc.)

We present a male patient with sporadic Aarskog syndrome, cleft palate, mild intellectual disability, and autism spectrum disorder (ASD). A submicroscopic discontiguous deletion was detected on chromosome Xp11.2 encompassing FGD1, FAM120C, and PHF8. That the deletion encompassed FGD1 (exons 2-8) explains the Aarskog features while the deletion of PHF8 most likely explains the cleft palate and mild intellectual disability. We identify FAM120C as a novel X-linked candidate gene for autism for two reasons: first, a larger deletion encompassing FAM120C segregates with autism in a previously reported family and second, there is recent evidence that FAM120C interacts with CYFIP1, part of the FMRP (Fragile X Mental Retardation Protein) network. In the current study, resequencing of FAM120C in 87 Belgian male patients with autism spectrum disorder identified no novel mutations. Expression of Fam120c in mouse tissues showed enriched expression in pituitary, cerebellum, cortex, and pancreatic islets of Langerhans. Additionally, we found a cortical expression pattern of Fam120c similar to that of Fmr1. In conclusion, FAM120C is a novel candidate gene for autism spectrum disorder based on genetic evidence and the brain expression pattern. Thereby we highlight a role for FMRP network genes in ASD., (© 2014 Wiley Periodicals, Inc.)