Diagnostic yield of microarrays in individuals with non-syndromic developmental delay and intellectual disability.

BACKGROUND: Intellectual disability (ID), or developmental delay (DD) when the individual is yet under 5 years of age, is evident before 18 years of age and is characterised by significant limitations in both intellectual functioning and adaptive behaviour. ID/DD may be clinically classified as syndromic or non-syndromic. Genomic copy number variations (CNVs) constitute a well-established aetiological subgroup of ID/DD. Overall diagnostic yield of microarrays is estimated at 10-25% for ID/DD, especially higher when particular clinical features that render the condition syndromic accompany. METHODS: In this study, we aimed to investigate the diagnostic yield of microarrays in the subgroup of individuals with non-syndromic ID/DD (NSID/NSDD). A total of 302 NSID/NSDD individuals who have undergone microarray analysis between October 2013 and April 2020 were included. Accompanying clinical data, including head circumference, delayed developmental areas, seizures and behavioural problems were collected and analysed separately in NSID and NSDD subgroups. RESULTS: The diagnostic yield of microarray analyses in NSID/NSDD was determined as 10.9% in NSID (10.7%) and in NSDD (11.1%). Presence of behavioural and epileptic problems did not contribute to the diagnostic yield. However, in the presence of macrocephaly, the contribution to diagnostic yield was statistically significant particularly in NSDD group. The most common pathogenic CNVs involved chromosomes 16, 15 and X. Lastly, we propose a Xq21.32q22.1 deletion as likely pathogenic in a child with isolated language delay and accompanying seizures. CONCLUSIONS: Particularly in neurodevelopmental diseases, microarrays are useful for establishing the diagnosis and detecting novel susceptibility regions. Future studies would accurately classify the herein presented variants of uncertain significance CNVs as pathogenic or benign.

Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability.

BACKGROUND: Aetiological diagnosis in non-syndromic intellectual disability (NSID) still poses a diagnostic challenge to clinicians. METHODS: Screening is currently achieved by chromosomal microarrays followed by whole-exome sequencing (WES). In search for the aetiological yield of WES in patients with NSID, 59 unrelated patients were studied. RESULTS: Among the 59 patients, 44 (74.6%) were from consanguineous unions. Epilepsy was present in 11 (37.9%), behavioural problems in 12 (41.4%) and autistic features in 14 (48.3%). WES analysis resulted in molecular diagnosis in 29 patients (49.2%). Some of the genes were specific for nervous system functioning, like HERC1, TBC1D7, LINS, HECW2, DEAF1, HNMT, DLG3, NRXN1 and HUWE1. Others were ubiquitously expressed genes involved in fundamental cellular processes, like IARS, UBE3A, COQ4, TAF1, SETBP1, ARV1, ZC4H2, KAT6A, ASXL3, THOC6, HNRNPH2, TUBA8 and KIF1A. Twenty-two (75.8%) were consanguineously married; however, only 12 (41.4%) of the detected genes caused autosomal recessive phenotypes. CONCLUSIONS: This cohort suggests that recessive genes probably represent an actually smaller subgroup of NSID, even among families with consanguinity. Although in societies with high consanguinity rates, considering the recessive inheritance first seems to be an advantageous strategy, de novo mutations in autosomal dominantly expressed genes represent the major aetiological group in patients with NSID, even among those patients from consanguineous families.

An eight-case 1q21 region series: novel aberrations and clinical variability with new features.

BACKGROUND: Rearrangement of the 1q21 region of chromosome 1 manifests as multiple phenotypes, including microcephaly, intellectual disability, dysmorphic facial features, eye abnormalities, cardiac defects, genitourinary anomalies, autism spectrum disorder, psychiatric conditions and seizures. Herein, we describe eight patients with 1q21 deletion and duplication syndromes, and novel deletions and findings. METHODS: Chromosomal microarray analysis was performed to identify the existence of copy number variation. Quantitative polymerase chain reaction was applied using specific primers for the control and 1q21 region of chromosome 1. Mutational analysis was performed in case 5 using direct genomic sequencing for exons 1-6 in RBM8A. RESULTS: Copy number variation analysis identified seven deletions and one duplication of the 1q21 region in the eight patients. In addition, four variations were de novo, and two deletions are reported here for the first time. One of the cases (case 7) presents moderate intellectual disability and dysmorphic facial findings, whereas chromosomal microarray analysis showed that case 7 had an 889-kb deletion in the 1q21 proximal region (GPR89A, PDZK1, CD160, POLR3C and NBPF12). CONCLUSION: Although the deletion in case 5 did not include the thrombocytopenia-absent radius syndrome critical region or the RBM8A gene, he had pectoral muscle hypoplasia, radius and humerus hypoplasia and short curved ribs, which are indicative of a potential thrombocytopenia-absent radius region modifier. The findings in case 7 suggest that the proximal part of the 1q21 microdeletion syndrome region might be very important for the onset of clinical manifestations. Some novel findings were observed in the presented cases, such as radius and humerus hypoplasia and brain stem hypoplasia. The presented findings expand the spectrum of 1q21 aberrations and provide evidence of genotype-phenotype correlations for this region.

Three cases of spondyloenchondrodysplasia (SPENCD) with systemic lupus erythematosus: a case series and review of the literature.

Spondyloenchondrodysplasia (SPENCD) is a rare autosomal recessive skeletal dysplasia caused by recessive mutations in the ACP5 gene, and it is characterized by the persistence of chondroid tissue islands within the bone. The clinical spectrum of SPENCD includes neurological involvement and immune dysfunction, such as systemic lupus erythematosus (SLE). To date, there are only 12 reported cases of SPENCD associated with SLE in the literature; however, detailed clinical follow-up data is absent for this comorbidity. This report presents clinical and laboratory data of three patients diagnosed with SPENCD-associated SLE. All three patients had short stature, arthralgia/arthritis, lupus nephritis, hypocomplementemia, and positive autoantibodies, including anti-nuclear and anti-dsDNA antibodies. Two patients exhibited class IV and one patient exhibited class V lupus nephritis. The early recognition of SPENCD is imperative, and this condition should be considered in patients with SLE, particularly in individuals with short stature and skeletal abnormalities. The cases presented here demonstrate that timely diagnosis and follow-up are key factors for the successful management of these conditions.

Parental factors in prenatal decision making and the impact of prenatal genetic counseling: a study on Turkish families.

OBJECTIVE: This study explored the social factors affecting prenatal decision making, the impact of genetic counseling on prenatal decision making, and how genetic counseling is perceived by Turkish women. METHOD: A standardized questionnaire was given to 231 patients, before and after genetic counseling, at Hacettepe University Ihsan Dogramaci Children's Hospital in 2007-2008. RESULTS: The level of education was an important factor both in prenatal decision making and in the patients' perception of genetic counseling. Decisions of pregnancy termination differed by geographic region of referral and history of healthy children but the differences were not statistically significant. The decisions were not influenced by poor obstetric history, number and sex of previous children, and disability of previous children. CONCLUSION: The level of education and the geographic region of referral in Turkey had an effect on the prenatal decisions and on the amount of prenatal genetic counseling received by the individuals.

Neurochemical evaluation of brain function with 1H magnetic resonance spectroscopy in patients with fragile X syndrome.

Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and (1)H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls (P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS.

Pulmonary agenesis and pulmonary sling anomaly in an infant with Down syndrome.

Pulmonary agenesis is a rare congenital anomaly presenting with normal karyotype in most of the cases. Rarely pulmonary agenesis is associated with chromosomal abnormalities and other genetic disorders such as Oculo-auriculo-vertebral spectrum, VACTERL association and velo-cardio-facial syndrome. This report presents a patient with pulmonary agenesis, pulmonary sling anomaly and Down syndrome.

Mucolipidosis type III in an adolescent presenting with atypical facial features and skeletal deformities.

Mucolipidosis type III (MLIII) (MIM# 252600) is an uncommon autosomal recessive disorder that results from deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The enzymatic defect results in deficiencies of lysosomal degradative enzymes with concomitant intracellular accumulation of both partly degraded glycosaminoglycans and sphingolipids leading to clinical manifestations such as short stature, developmental delay and other structural abnormalities. The diagnosis is challenging since musculoskeletal presentation may mimic some of the rheumatic and metabolic disorders. We herein report on a 13-year-old adolescent who was admitted to our rheumatology clinic because of progressive joint stiffness and deformities of her hands. The clinical and radiological findings led us to the diagnosis of MLIII despite negative urinary aminoglycosyaminoglycans. Therefore we decided to check for the presence of elevated activities of alpha-mannosidase and beta-hexosaminidase A+B in the plasma which was actually the case and confirmed the clinical diagnosis ofMLIII.

Clinical and molecular analysis of RASopathies in a group of Turkish patients.

The 'RASopathies' are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty-one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype-phenotype correlations in RASopathies are relatively independent from the ethnic population background.

Searching for Copy Number Changes in Nonsyndromic X-Linked Intellectual Disability.

Intellectual disability (ID) has a prevalence of 2-3% with 0.3% of the population being severely retarded. Etiology is heterogeneous, owing to numerous genetic and environmental factors. Underlying etiology remains undetermined in 75-80% of mildly disabled patients and 20-50% of those severely disabled. Twelve percent of all ID is thought to be X-linked (XLID). This study covers copy number analysis of some of the known XLID genes, using multiplex ligation-dependent probe amplification (MLPA) in 100 nonsyndromic patients. One of the patients was found to have duplication in all exons of MECP2 gene, and another had duplication in the fifth exon of TM4SF2/TSPAN7 gene. Affymetrix® 6.0 whole-genome SNP microarray confirmed the duplication in MECP2 and showed duplication of exons 2-7 in TM4SF2/TSPAN7, respectively. MECP2 duplication has recently been recognized as a syndromic cause of XLID in males, whereas duplications in TM4SF2/TSPAN7 are yet to be determined as a cause of XLID. Being an efficient, rapid, easy-to-perform, easy-to-interpret, and cost-effective method of copy number analysis of specific DNA sequences, MLPA presents wide clinical utility and may be included in diagnostic workup of ID, particularly when microarrays are unavailable as a first-line approach.

Opinions of Turkish physicians towards termination of pregnancy for fetal disorders.

Termination of pregnancy (ToP) raises ethical dilemmas. Although ToP for fetal disorders is commonly approved by health professionals, their opinions and attitudes are influenced by a diversity of cultural contexts. The aim of the study is to investigate Turkish physicians' opinions on ToP for fetal disease and the hypothesis is that their opinions are influenced by whether they face any disabilities of affected children or not. We aimed to survey by a questionnaire the opinions of Turkish physicians towards ToP for untreatable fetal disorders. A group of 250 subjects was included in the study. Physicians' approval of parents' decision for ToP was higher for disorders that they encounter more frequently during their daily work. Their opinions were not statistically different when compared for gender and marital status, however, having children of their own caused significant differences for some of the disorders. Approximately 65% of the participants responded that families alone should have the right to decide on ToP. The results confirm that health professionals may have differences in perception of severity of diseases, based on their clinical experience. Physicians encountering affected children more likely approve ToP for that particular disease.

Kabuki syndrome and trisomy 10p.

Kabuki syndrome (KS) (MIM 147920) is a multiple congenital anomalies/mental retardation syndrome of unknown cause. There is multisystem involvement of anomalies, including 1) unique facial features, 2) postnatal growth retardation, 3) mild-to-moderate mental retardation, 4) skeletal anomalies and 5) dermatoglyphic abnormalities. Kabuki syndrome remains a clinical diagnosis despite significant research on detection of the genetic cause. We present 10 patients with Kabuki syndrome with a brief overview of the syndrome. An additional male patient and his affected aunt, both with trisomy 10p due to unbalanced segregation of a familial translocation, are also discussed for overlapping features and differential clinical diagnosis of the two conditions. Considering a significant overlap in clinical pictures of Kabuki syndrome and trisomy 10p in these two patients, as well as the previous patients with chromosomal abnormalities, we conclude that chromosome analysis is an important step in clinical work-up of patients with Kabuki syndrome.

Neocentric small supernumerary marker chromosomes (sSMC)--three more cases and review of the literature.

Here we report on three new patients with neocentric small supernumerary marker chromosomes (sSMC) derived from chromosome 2, 13 and 15, respectively. The sSMC(13) and sSMC(15) had inverted duplicated shapes and the sSMC(2) a ring chromosome shape. All three cases were clinically severely abnormal. A review of the available sSMC literature revealed that up to the present 73 neocentric sSMC cases including these three new cases have been reported. Seven of these cases were not characterized morphologically; in the remainder, 80% had an inverted duplication, 17% a ring and 3% a minute shape. 81% of the reported neocentric sSMC carriers showed severe, 12% moderate and 8% no clinical abnormalities. In summary, we report three more neocentric sSMC cases, provide a review on all up to now published cases, highlight their special characteristics and compare them to centric sSMC.

Coexistent mosaic monosomy 21 and fragile X syndrome in a mentally retarded male patient.

Fragile X syndrome (FXS) is a well-recognized mental retardation syndrome with characteristic facial features and behavioural phenotype. Monosomy 21 is a rare cytogenetic aberration for which clinical features were incompletely defined since full monosomy 21 is incompatible with life. A 5-year-old male patient with FXS and low-grade mosaicism for full monosomy 21 (46,XY[96%]/45,XY,-21[4%]) is presented. He had lack of speech and severely impaired social skills, hyperactivity, stereotypical hand movements, a special interest towards moving colourful items and a short attention span for other objects around. He had macrocephaly, a rather long face, prominent occiput and prominent midface, retrognathia, down-slanting palpebral fissures, hypertelorism and cup-shaped, posteriorly rotated and low-set ears. Full monosomy in the aberrant cell line was proven by whole chromosome painting. FXS was previously reported to accompany sex chromosome aneuploidies; however, to the best of our knowledge, the present patient is the first FXS patient with an aberration involving autosomes. He contributes to the current knowledge on monosomy 21 phenotype, having dysmorphic facial findings despite the concurrent phenotypic expression of the FXS. As a last conclusion, cytogenetic analysis must be done to all mentally retarded patients with minor dysmorphic features.

A multidisciplinary approach to the management of individuals with fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Since the identification of the responsible gene (FMR1) and its protein (FMRP), there has been enormous progress in both clinical and pathogenetic research on the neurobehavioural aspects of the condition. However, studies regarding other medical problems anticipated in individuals with FXS are limited. A multidisciplinary study evaluating various causes of morbidity in the same group has not been published yet. METHODS: Twenty-four boys with FXS full mutation were recruited out of a larger group of 103 diagnosed in one centre over the past 10 years. Ear nose and throat, eye and cardiac examinations were performed in addition to routine cognitive, behavioural, neurological and speech and language assessments. RESULTS: The average IQ score was 49.8 +/- 20 (range 25-90). There were four patients (18%) with IQ above 70. Using DSM-IV, attention deficit hyperactivity disorder was diagnosed in five boys out of 22 examined (23%), while 32% were diagnosed with pervasive developmental disorder. The seizure frequency was 17%. A psychiatric disorder was diagnosed in six out of eight boys with electroencephalogram abnormalities (75%). Minimal conductive hearing loss was found in five (5/22) patients. There was significant delay in both expressive and receptive language skills. Ocular findings were refractive errors (13%) and strabismus (4.4%). Mitral valve prolapsus (MVP) was observed in 3/22 (13.7%) patients and aortic annulus dilatation was present in 2/22 (9%) patients. CONCLUSIONS: Frequency of psychiatric diagnoses made with DSM-IV were in parallel to those reported in the literature. Comorbidity of seizures and psychiatric disorders was noteworthy. The percentage of 'high-functioning' full mutation males supports the previous observations. Ear nose and throat and eye examination revealed remarkably lower prevalence of abnormal findings than reported. MVP was slightly less frequent compared with the single study in the literature. Age at the time of examination had an effect on the outcome of cardiac evaluation. These findings will guide us in future management of the group of patients followed in our institution. The protocol applied provides an applicable outline for multidisciplinary institutional settings dealing with individuals with FXS.

Prenatal diagnosis in three cases of iniencephaly with unusual postmortem findings.

Iniencephaly is a rare and lethal congenital malformation of the neural tube characterized by occipital bone defect, cervical dysraphism, fixed retroflexion of the fetal head and severe lordosis of the cervicothoracic spine. The etiology is unknown. Prenatally diagnosed cases of iniencephaly are rare because careful and early ultrasonographic evaluation is necessary. We present three cases of iniencephaly prenatally diagnosed by sonography at 20-22 weeks' gestation in which therapeutic abortion was induced. The sonographic findings were compatible with the postmortem findings. The present cases of iniencephaly were found to carry unusual associated malformations such as two lobes in the right lung and chorangiosis of the placenta. Only hypoplastic lungs have been reported by previous authors. We also studied the 677C-->T mutation on the methylenetetrahydrofolate reductase gene in the parents in one of the present cases. The mother was found to be heterozygous for the 677CT polymorphism.

Familial microtia in four generations with variable expressivity and incomplete penetrance in association with type I syndactyly.

Familial microtia with external ear canal atresia and conductive deafness is rarely reported. Autosomal dominant and recessive inheritance have been suggested depending on various family reports. Cases with other malformations in addition to microtia have been described, although the microtia generally is an isolated finding. Here we report a family with microtia, external auditory canal atresia and conductive deafness in four generations. The mode of inheritance of the disease was autosomal dominant within this family. Also, variable expressivity, incomplete penetrance and generation skipping are evident in the pedigree. Association of microtia with type I syndactyly, which has never been reported previously, was present in the index case.

Myelodysplastic syndrome associated with monosomy 7 in a child with Bloom syndrome.

Bloom syndrome is a genomic instability syndrome associated with predisposition to development of various types of malignancy. In this report, we described a 7-year-old boy with Bloom syndrome (BS) and myelodysplastic syndrome (MDS) associated with monosomy 7 and loss of the Y chromosome. To our knowledge, this was the first case with BS showing monosomy 7 and MDS during the early childhood period.