Abstract Pathogenic variants in the MBTPS1 gene encoding the Site 1 protease have been described so far only in one growth retarded patients with skeletal deformities, large ears, a triangular face reminiscent to Silver–Russell syndrome (SRS), and elevated blood lysosomal enzymes. We now report on the identification of a second adult patient homozygous for one of the two published pathogenic MBTPS1 variants (p.Asp365Gly) by Whole Exome Sequencing (WES), and a comparable phenotype. With this case,...
Fri Aug 28, 2020 19:10
Abstract Bi‐allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley–Salih–Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.
Mon Aug 31, 2020 11:13
Abstract There are limited data on the longitudinal frequency and severity of the symptoms and complications of achondroplasia. We undertook a retrospective electronic chart review of 114 patients to develop a more thorough understanding of the lifetime impact of achondroplasia. Craniocervical stenosis (involving the foramen magnum with or without cervical vertebrae C1 and/or C2) was noted in nearly 50% of patients with craniovertebral junction imaging; however, corrective decompression surgery...
Mon Aug 31, 2020 11:15
Abstract EVEN‐PLUS syndrome is a rare condition characterized by its involvement of the Epiphyses, Vertebrae, Ears, and Nose, PLUS other associated findings. We report here the fifth case of EVEN‐PLUS syndrome with novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene identified through whole‐exome sequencing. The patient is the first male known to be affected and presented with additional features not previously described with EVEN‐PLUS syndrome. These features include...
Tue Sep 01, 2020 16:44
Abstract The CAMK2B gene encodes the β‐subunit of calcium/calmodulin‐dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p.(P139L). This case report describes a 22‐year‐old patient with this recurrent variant, who presents with severe intellectual disability, absence...
Tue Sep 01, 2020 21:10
Abstract Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In...
Fri Sep 04, 2020 13:07
Abstract Chromosomal 7q31 deletions have been described in individuals with variable neurodevelopmental phenotypes including speech and language impairment. These copy number variants usually encompass FOXP2, haploinsufficiency of which represents a widely acknowledged cause for specific speech and language disorders. By chromosomal microarray analysis we identified a 4.7 Mb microdeletion at 7q31.2q31.31 downstream of FOXP2 in three family members presenting with variable speech, language and neurodevelopmental...
Fri Sep 04, 2020 13:07
Abstract Gastroschisis and omphalocele are the two most common abdominal wall birth defects, and epidemiologic characteristics and frequency of occurrence as part of a syndromic condition suggest distinct etiologies between the two defects. We assessed complex patterns of defect co‐occurrence with these defects separately using the Texas Birth Defects Registry. We used co‐occurring defect analysis (CODA) to compute adjusted observed‐to‐expected (O/E) ratios for all observed birth defect patterns....
Fri Sep 04, 2020 13:07
ABSTRACT Robinow syndrome (RS) is a genetically heterogeneous skeletal dysplasia with recent reports suggesting an osteosclerotic form of the disease. We endeavored to investigate the full spectrum of skeletal anomalies in a genetically diverse cohort of RS patients with a focus on the bone micro‐architecture. Seven individuals with molecularly confirmed RS, including four with DVL1 variants and single individuals with variants in WNT5A, ROR2, and GPC4 underwent a musculoskeletal focused physical...
Sat Sep 05, 2020 14:45
Abstract Biallelic mutations in the LARP7 gene have been recently shown to cause Alazami syndrome, a rare condition characterized by short stature, intellectual disability, and peculiar facial dysmorphisms. To date, only 24 cases have been reported. Here, we describe two brothers initially suspected to have Smith–Lemli–Opitz syndrome, in whom clinical exome sequencing detected a novel homozygous truncating variant in LARP7. These cases expand the phenotypic spectrum of Alazami syndrome to include...
Sat Sep 05, 2020 14:49
Abstract A study of the prevalence rates for selected isolated non‐Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs‐Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997–2016. Since...
Mon Sep 07, 2020 13:56
ABSTRACT Oculo‐auriculo‐vertebral spectrum (hemifacial microsomia/OAVS, OMIM #164210) is a heterogenous and congenital condition caused by a morphogenesis defect of the first and second pharyngeal arches. Etiology includes unknown genetic, environmental factors and chromosomal alterations, which 22q11.2 region is the most frequently reported. Several candidate genes for OAVS have been proposed; however, none has been confirmed as causative of the phenotype. This review aims to sum up all clinical...
Mon Sep 07, 2020 14:02
Abstract Proximal interstitial deletions of chromosome 9p13 have been described only in a few patients with developmental delay, moderate intellectual disability, craniofacial dysmorphism, short stature, genital anomalies, and precocious puberty. To corroborate and expand these findings, we report on two novel syndromic male patients with 9p13 deletions suffering from a similar form of tremor and compare them with literature data. Despite genomic variability in deletion sizes, all patients displayed...
Tue Sep 08, 2020 16:14
Abstract Cerebellofaciodental syndrome (MIM #616202) is an autosomal recessive condition characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features, and short stature. To date, eight patients carrying biallelic BRF1 variants have been reported. Here, we describe two siblings with congenital microcephaly and corpus callosum hypoplasia, pre and postnatal growth retardation, congenital heart defect and severe global developmental delay. We also detected additional...
Tue Sep 08, 2020 16:14
Abstract Bi‐allelic loss‐of‐function variants in LAMC3, encoding extracellular matrix protein laminin gamma 3, represent a rare cause of occipital polymicrogyria with epilepsy, developmental delay and cognitive impairment. So far, only five families have been reported. We now identified a novel, homozygous splice variant in LAMC3 in an individual with an unusual manifestation of cortical malformation. She presented with polymicrogyria in the frontal but not the occipital lobes, with adult‐onset...
Wed Sep 09, 2020 14:15
Abstract Genetic diagnosis depends on having available tissue to test. This can be important for many reasons, such as related to familial diagnosis in the case of another pregnancy. When blood or DNA samples from affected family members are not available, accurate prenatal diagnosis may be much more difficult and hence additional effort may be needed to obtain a genetic diagnosis in such families. We report two families with suspected monogenic disorders where attempts were made to establish the...
Wed Sep 09, 2020 14:16
Abstract Down syndrome (DS) is associated with a complex respiratory phenotype, including obstructive sleep apnea syndrome (OSAS). The study explored parent‐reported prevalence and presentation of OSAS symptoms in children and adolescents with DS in Ireland. It also investigated treatment and compliance in those who have OSAS. A cross‐sectional survey was distributed to parents registered with Down Syndrome Ireland (DSI) (n = 1,343). Data was collated and analyzed using SPSS v23. The response rate...
Wed Sep 09, 2020 14:17
ABSTRACT The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (~23% of patients), or suggestive clinical features. We describe four...
Wed Sep 09, 2020 14:18
Abstract Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) caused by germline de novo variants in FBXO11 was recently recognized as a novel intellectual disability (ID) syndrome through reverse phenotyping after whole‐exome sequencing (WES). Fewer than 50 disease‐causing de novo FBXO11 variants in IDDFBA are reported thus far. Here, we present the first report of a family showing autosomal dominantly inherited IDDFBA, harboring a novel heterozygous...
Wed Sep 09, 2020 14:18
Abstract NFIB (Nuclear Factor I B) haploinsufficiency has recently been identified as a cause of intellectual disability and macrocephaly. Here we describe two patients with pathogenic variants in NFIB. The first is a 6‐year‐old Latino male with developmental delays, mild hypotonia, facial anomalies, and brain magnetic resonance imaging findings comprising mild thinning of the corpus callosum, with more marked thinning of the splenium and blunting of the rostrum and cavum septum pellucidum. Exome...
Wed Sep 09, 2020 18:18
Abstract Hereditary mucoepithelial dysplasia (HMD) is an uncommon autosomal dominant disease affecting skin, mucosae, hair, eyes, and lungs. Prominent clinical features include non‐scarring alopecia, mucosal erythema, perineal erythematous intertrigo, and involvement of the conjunctival mucosa. To date, 20 familial or sporadic HMD cases have been described, most of them originating from Caucasian ethnic groups. In this study, a novel HMD pedigree, including an affected father and his daughter, is...
Wed Sep 09, 2020 18:18
Abstract Ehlers‐Danlos Syndromes (EDS) and related Hypermobility Spectrum Disorders (HSD) are debilitating connective tissue disorders that feature a prominent pain component for which there are limited therapeutic options for pain management. Consequently, many patients try various non‐prescribed treatments, including complementary and alternative therapies that have not been well studied in the EDS/HSD patient population. We surveyed over 500 individuals through the EDS Society who reported having...
Thu Sep 10, 2020 13:33
Abstract Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2‐year‐old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio‐exome sequencing detected compound heterozygous variants...
Thu Sep 10, 2020 14:08
Abstract Patients with Down syndrome (DS) often have a high occurrence of obstructive sleep apnea‐hypopnea (OSA) syndrome. We studied a large cohort of adults with DS attended due to clinical suspicion of OSA. A standardized questionnaire and full medical assessment were conducted, including a sleep study. One hundred and fifty‐seven DS individuals were studied, with a mean ± SD age of 36 ± 10 years, 40.7% women, BMI 29.4 ± 5.6 kg/m2. The main clinical symptom was daytime sleepiness (64.9%). A sleep...
Thu Sep 10, 2020 14:09
Abstract Kinase D‐interacting substrate of 220 kDa (KIDINS220) is a transmembrane protein playing integral role in growth mediating pathways in the nervous and cardiovascular systems. KIDINS220 heterozygous truncating variants that affect the protein's C‐terminus have been associated with a phenotype, so far described only in few unrelated children, including spastic paraplegia, intellectual disability, nystagmus, and obesity. More recently, a homozygous, more N‐terminal truncating variant in KIDINS220...
Thu Sep 10, 2020 14:19
Abstract Wolf–Hirschhorn syndrome (WHS) (OMIM#194190) is a contiguous gene syndrome with estimated prevalence being around 1 in 50,000 births. The syndrome is caused by deletion of a critical region (Wolf–Hirschhorn Syndrome Critical region—WHSCR) on chromosome 4p16.3. Its core features are typical facial gestalt, growth retardation, intellectual disability, or developmental delay and seizures. We describe four patients, each highlighting a different aspect of this syndrome. One patient was detected...
Thu Sep 10, 2020 20:38
Thu Sep 10, 2020 20:44
Abstract Mild clinical phenotypes of ataxia‐telangiectasia (variant A‐T) are associated with biallelic ATM variants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A‐T. Studies on the pathogenicity of the germline splicing ATM variant c.1066‐6T>G have provided conflicting results. Using whole‐exome sequencing, we identified two...
Fri Sep 11, 2020 20:48
Abstract BACKGROUND Persons with Down syndrome (DS) are presumed to be at high risk of severe CoVID‐19, due to immune dysregulation and often compromised cardiopulmonary function. Aim of the present study is to assess epidemiological and clinical characteristics of individuals with DS deceased in Italian hospitals with CoVID‐19. METHODS We used a nationwide database of 3,438 patients deceased with RT‐PCR‐confirmed SARS‐CoV‐2 infection in Italy (10.4% of all deaths with CoVID‐19 in the country...
Sat Sep 12, 2020 14:17
Abstract We identified a novel nonsense de novo pathogenic variant of the NEXMIF gene in a 29 year‐old female patient with refractory epilepsy and mild intellectual disability. The patient presented with episodic atypical absence status (AS), the longest duration of her seizures was approximately 36 hr. She also had occasional eyelid myoclonia during absence seizure. EEG highlighted a photosensitivity phenomenon and generalized epileptiform discharges that were induced by eye closure. Whole exome...
Mon Sep 14, 2020 11:18
Abstract Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as “recurrent constellations of embryonic malformations” (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more...
Mon Sep 14, 2020 11:28
Abstract Loeys‐Dietz syndrome (LDS), a connective tissue disorder characterized by its vascular, skeletal, craniofacial, and cutaneous manifestations is caused by mutations in one of six genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3). Until recently, all reported cases of LDS have been attributed to heterozygous pathogenic variants in these genes. Here, we report the first case of Loeys‐Dietz syndrome due to SMAD3 biallelic likely pathogenic variants in a 15‐year‐old male with classic Loeys‐Dietz...
Tue Sep 15, 2020 21:40
Cover Image © Andrey Prokhorov/iStockphoto
Tue Sep 15, 2020 15:56
Abstract Headache and neck pain (cervicalgia) are frequently reported among patients with joint hypermobility but the prevalence and scope of these symptoms has not been studied in the era of contemporary Ehlers‐Danlos and hypermobility disorder nosology. We performed a single‐center retrospective study on the incidence of head and neck symptoms in 140 patients with hypermobility disorders over a 2‐year period. Overall, 93 patients (66%) reported either headache or neck pain with 49 of those (53%)...
Thu Sep 17, 2020 13:04
Abstract Down syndrome is the most common chromosomal disorder, affecting 1/700 live births. Among the clinical findings, one constant concern is the high prevalence of visual disorders that, if left untreated, can negatively affect child development. The aim of this study was to determine the prevalence of ophthalmological findings among patients who attended an outpatient clinic for patients with Down syndrome in southern Brazil between 2005 and 2016. A cross‐sectional study including 1,207 patients...
Fri Sep 18, 2020 11:27
Abstract We present a family with three girls presenting similar dysmorphic features, including overgrowth, intellectual disability, macrocephaly, prominent forehead, midface retrusion, strabismus, and scoliosis. Both parents were unaffected, suggesting the presence of an autosomal recessive syndrome. Following exome sequencing, a heterozygous nonsense variant was identified in the NFIX gene in all three siblings. The father appeared to have a low‐grade (7%) mosaicism for this variant in his blood....
Fri Sep 18, 2020 11:28
Abstract Pitt–Hopkins syndrome (PTHS, MIM #610954) is a rare neurodevelopmental disease characterized by the association of intellectual disability, characteristic facial gestalt and episodes of abnormal and irregular breathing. PTHS is due to heterozygous loss‐of‐function variants in the TCF4 gene (transcription factor 4, MIM #602272) encoding for a basic helix–loop–helix transcription factor. TCF4 is highly expressed during early development of the nervous system, and it is involved in cellular...
Fri Sep 18, 2020 11:58
Abstract We report a patient with phenotypic semblance to the congenital microgastria‐limb reduction association (MLRD). Our patient presented with microgastria, bilateral upper limb anomalies, asplenia, solitary kidney, and mild micrognathia. In addition to the anomalies seen in our patient, MLRD has been associated with respiratory, cardiovascular, and central nervous system anomalies. MLRD is thought to arise from a developmental field defect during embryonic weeks five and six; however, no genetic...
Fri Sep 18, 2020 14:15
Abstract The aim of this study was to evaluate the oral, dental, and craniofacial features of individuals affected by the chronic forms of acid sphingomyelinase deficiency (ASMD). This study comprised a sample of adult and pediatric patients (n = 8) with chronic ASMD. The individuals underwent oral examinations to evaluate the occurrence of caries, as well as full‐mouth periodontal examinations, to assess the occurrence and severity of periodontal diseases. Panoramic and profile radiographs were...
Fri Sep 18, 2020 15:38
Abstract Differences in sex development (DSD) are a group of rare conditions involving genes, hormones and reproductive organs, including genitals. Although these disorders are common, information about the molecular causes remain limited. Many genes have been identified in association with DSD but in many cases the causative gene could not be identified. The Lhx9 gene has been studied in mice and birds, and biallelic mutations in this gene have been found to cause 46,XY DSD and limb abnormalities....
Sat Sep 19, 2020 11:10
Abstract Blepharophimosis‐ptosis‐intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis,...
Sat Sep 19, 2020 11:11
Abstract Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. The estimated incidence ranges from 1 in 4,500–5,500 for strictly defined “ambiguous genitalia” to 1 in 300 or higher when a broader definition is implemented. In this study, we aim to define DSD phenotypes encountered in a large heterogeneous cohort of molecularly characterized Mendelian disorders in a single center. Data were retrieved for patients with documented...
Sat Sep 19, 2020 11:24
Abstract Rett syndrome (RTT, MIM * 312750) is an X‐linked neurodevelopmental disorder caused by pathogenic variants at the Xq28 region involving the gene methyl‐CpG‐binding protein 2 (MECP2, MIM * 300005). The spectrum of MECP2‐related phenotypes is wide and it ranges from asymptomatic female carriers to severe neonatal‐onset encephalopathy in males. Abnormal breathing represents one of the leading features, but today little is known about polysomnographic features in RTT females; no data are available...
Mon Sep 21, 2020 13:11
Abstract Limb reduction defects (LRDs) that affect multiple limbs are considered to be more often heritable, but only few studies have substantiated this. We aimed to investigate if an etiological diagnosis (genetic disorder or clinically recognizable disorder) is more likely to be made when multiple limbs are affected compared to when only one limb is affected. We used data from EUROCAT Northern Netherlands and included 391 fetuses and children with LRDs born in 1981–2017. Cases were classified...
Mon Sep 21, 2020 13:11
Abstract It has been estimated that 10–15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4–51 years were seen for neuropsychological screening. Eight had autosomal‐dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal‐recessive RS (NXN, n = 2; ROR2, n = 2),...
Mon Sep 21, 2020 13:11
Abstract Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X‐linked Opitz G/BBB syndrome with MID1 mutations who have...
Mon Sep 21, 2020 13:11
Abstract Recently, the genetic cause of HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities) was identified as biallelic pathogenic variants in P4HTM, which encodes an atypical member of the prolyl 4‐hydroxylases (P4Hs) family of enzymes. We report seven patients from four new families in whom HIDEA was only diagnosed after whole‐exome sequencing (WES) revealed novel disease‐causing variants in P4HTM. We note the variable phenotypic...
Wed Sep 23, 2020 12:20
Abstract Robinow syndrome, a rare genetic disorder, is characterized by skeletal dysplasia with, among other anomalies, extremity and hand anomalies. There is locus heterogeneity and both dominant and recessive inheritance. A detailed description of associated extremity and hand anomalies does not currently exist due to the rarity of this syndrome. This study seeks to document the hand anomalies present in Robinow syndrome to allow for improved rates of timely and accurate diagnosis. A focused assessment...
Fri Sep 25, 2020 11:30
Abstract We report clinical and radiological features of a patient born with an isolated skull malformation of caput membranaceum and partial bicoronal craniosynostosis with a novel, de novo heterozygous missense variant in ZIC1 [NM_003412.3:c.1183C>G, p.(Pro395Ala)]. Caput membranaceum, or boneless skull, is a rare manifestation of skull ossification defect. It can result from an isolated, enlarged parietal foramina or it can present as part of skeletal dysplasia syndromes associated with poor...
Fri Sep 25, 2020 11:34
Abstract Constitutional ring chromosome 9, r(9), is a rare chromosomal disorder. Cytogenomic analyses by karyotyping, array comparative genomic hybridization (aCGH) and whole genome sequencing (WGS) were performed in a patient of r(9). Karyotyping detected a mosaic pattern of r(9) and monosomy 9 in 83% and 17% of cells, respectively. aCGH detected subtelomeric deletions of 407 kb at 9p24.3 and 884 kb at 9q34.3 and an interstitial duplication of 5.879 Mb at 9q33.2q34.11. WGS revealed double strand...
Sat Sep 26, 2020 22:14
Abstract Gaucher disease, a lysosomal storage disorder and hemophagocytic lymphohistiocytosis (HLH), a disorder of the immune system, have several overlapping clinical features including cytopenias, elevated serum ferritin, and splenomegaly. Prior reports of acute infantile neuronopathic, Type 2 Gaucher disease manifesting with signs of HLH have been published. Here we describe an adult patient who was initially suspected of having HLH, and was treated with a 10‐day course of etoposide and a 5‐day...
Sun Sep 27, 2020 20:10
Abstract Variants in PPP1R21 were recently found to be associated with an autosomal recessive intellectual disability syndrome in 9 individuals. Our patient, the oldest among the known subjects affected by PPP1R21‐related syndrome, manifested intellectual disability, short stature, congenital ataxia with cerebellar vermis hypoplasia, generalized hypertrichosis, ulcerative keratitis, muscle weakness, progressive coarse appearance, macroglossia with fissured tongue, and deep palmar and plantar creases....
Sun Sep 27, 2020 20:11
Abstract Rubinstein–Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss‐of‐function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology....
Sun Sep 27, 2020 20:12
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