Blended Phenotype of Pelger-Huet Anomaly with Osteochondroma and Autosomal Recessive Deafness with Enlarged Vestibular Aqueduct

Pelger-Huet anomaly (PHA) is a benign hematological anomaly that is characterized by impaired lobulation of neutrophils with a coarse nuclear chromatin. Skeletal abnormalities may accompany this anomaly. Autosomal recessive deafness-4 (DFNB4) with enlarged vestibular aqueduct (EVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL). We report a case with SNHL, multiple skeletal anomalies including osteochondroma, developmental delay, and PHA. Molecular studies revealed a heterozygous pathogenic variant in the <i>LBR</i> gene and a homozygous likely pathogenic variant in the <i>SLC26A4</i> gene. Due to these 2 variants, he was diagnosed with PHA and DFNB4 with EVA. If goiter develops, DFNB4 with EVA is named Pendred syndrome (PDS), so the patient will be followed up for this condition, and in the current literature, there is no case with PDS and PHA co-existence either. PHA may be accompanied by multiple skeletal abnormalities. In our case, there is also concomitance with osteochondroma. Although these are independent and distinct diagnoses, we present this case due to the concomitance of these situations.

Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic KRAS Variation

<b><i>Introduction:</i></b> Germline pathogenic variations of the genes encoding the components of the Ras-MAPK pathway are found to be responsible for RASopathies, a clinically and genetically heterogeneous group of diseases. In this study, we aimed to present the results of patients genetically investigated for RASopathy-related mutations in our Genetic Diagnosis Center. <b><i>Methods:</i></b> The results of 51 unrelated probands with RASopathy and 4 affected relatives (31 male, 24 female; mean age: 9.327 ± 8.214) were included in this study. Mutation screening was performed on DNA samples from peripheral blood of the patients either by Sanger sequencing of <i>PTPN11</i> hotspot regions (10/51 probands), or by a targeted amplicon next-generation sequencing panel (41/51 probands) covering the exonic regions of <i>BRAF</i>, <i>CBL</i>, <i>HRAS</i>, <i>KRAS</i>, <i>LZTR1</i>, <i>MAP2K1</i>, <i>MAP2K2</i>, <i>NF1</i>, <i>NRAS</i>, <i>PTPN11</i>, <i>RAF1</i>, <i>RASA2</i>, <i>RIT1</i>, <i>SHOC2</i>, <i>SOS1</i>, <i>SOS2</i>, <i>SPRED1</i>, and <i>KAT6B</i> genes. <b><i>Results:</i></b> Pathogenic/likely pathogenic variations found in 22 out of 51 probands (43.13%) and their 4 affected family members were located in <i>PTPN11</i>, <i>BRAF</i>, <i>KRAS</i>, <i>NF1</i>, <i>RAF1</i>, <i>SOS1</i>, and <i>SHOC2</i> genes. The c.148A&#x3e;C (p.Thr50Pro) variation in the <i>KRAS</i> gene was a novel variant detected in a sibling in our patient cohort. We found supportive evidence for the pathogenicity of the <i>NF1</i> gene c.5606G&#x3e;T (p.Gly1869Val) variation which we defined in an affected boy who inherited the mutation from his affected father. <b><i>Conclusion:</i></b> Although <i>PTPN11</i> is the most frequently mutated gene in our patient cohort, as in most previous reports, different mutation distribution among the other genes studied motivates the use of a next-generation sequencing gene panel including the possible responsible genes.

What Can We Learn from the Parents of Children Affected with Mucopolysaccharidosis Type III-A in Israel?

Sanfilippo Syndrome, or mucopolysaccharidosis type III (MPS III), is a group of autosomal-recessive lysosomal storage disorders leading to tissue accumulation of heparan sulfate. MPS III is caused by deficiency in one of 4 enzymes involved in lysosomal degradation of heparan sulfate. Based on the relevant enzyme deficiency, 4 types have been recognized. MPS III constitutes a progressive neurodegenerative and systemic disorder. Parents of children diagnosed with MPS III were interviewed using a retrospective questionnaire based on the known clinical manifestations of MPS III. Eight patients from 4 unrelated families of varied ethnic origin were included. All children were diagnosed with MPS type III-A. Average age at diagnosis was 6.1 years. The most common early clinical manifestations leading to parental suspicion of illness were speech delay and coarse facial features. All children were reported to have global developmental delay, sleep disorders, recurrent infections, hyperactivity, and decreased hearing. The time from first medical inquiry until diagnosis was over 2 years on average, consistent with the delay in diagnosis described in the literature. MPS III children frequently undergo early and repeated ear, nose and throat surgeries, thus we suggest that a high index of suspicion is warranted in relevant clinical circumstances.

Clinical Implications of Chromosome 16 Copy Number Variation

Chromosome 16 is one of the gene-rich chromosomes; however, approximately 10% of the chromosome 16 sequence is composed of segmental copies, which renders this chromosome instable and predisposes it to rearrangements via frequent nonallelic homologous recombination. Microarray technologies have enabled the analysis of copy number variations (CNV), which may be associated with the risk of developing complex diseases. Through comparative genomic hybridisation in 1,298 patients, we detected 18 cases with chromosome 16 CNV. We identified 2recurrent CNV regions, including 1 at 16p13.11 in 4 patients and another at 16p11.2 in 7 patients. We also detected atypical chromosome 16 rearrangements in 7 patients. Furthermore, we noted an increased frequency of co-occurring genomic changes, supporting the two-hit hypothesis to explain the phenotypic variability in the clinical presentation of CNV syndromes. Our findings can contribute to the creation of a chromosome 16 disease map based on regions that may be associated with disease development.

Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review

Bi-allelic mutations in the <i>TUBGCP4</i> gene have been recently associated with autosomal recessive microcephaly with chorioretinopathy. However, little is known about the genotype-phenotype characteristics of this disorder. Here, we describe a 5-year-old male patient with autism and a normal occipitofrontal circumference. No retinal abnormalities were observed. Brain MRI revealed the presence of enlarged sheaths of both tortuous optic nerves; both eyes had shorter axial lengths. Whole-exome sequencing in trio revealed synonymous <i>TUBGCP4</i> variants in homozygous state: c.1746G&#x3e;T; p.Leu582=. This synonymous variant has been previously described and probably leads to skipping of exon 16 of <i>TUBGCP4</i>. These results broaden the clinical spectrum of this new syndrome and suggest that <i>TUBGCP4</i> bi-allelic mutations may underlie complex neurodevelopmental disorders.

Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts

We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (<i>TREX1</i>, <i>RNASEH2A</i>, <i>RNASEH2B</i>, <i>RNASEH2C</i>, <i>SAMHD1</i>, <i>ADAR</i>, <i>IFIH</i>, <i>LSM11</i>, <i>RNU7-1</i>) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the <i>SAMHD1</i> gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a <i>SAMHD1</i> mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.

KMT2B-Related Dystonia: Challenges in Diagnosis and Treatment

In this study, we report the first known Turkish case of a novel nonsense mutation c.2453dupT (p.M818fs*28) in the <i>KMT2B</i> (NM_014727.2) gene diagnosed in a male patient with <i>KMT2B</i>-related dystonia (DYT-<i>KMT2B</i>, DYT-28, Dystonia*-28), which is a complex, childhood-onset, progressive, hereditary dystonia. The patient, who is followed up from 9 to 13 years of age, had dysmorphic features, developmental delay, short stature, and microcephaly, in addition to focal dystonia and hemichorea (in the right and left lower extremities). Generalized dystonia involving bulbar and cervical muscles, in addition to dystonic cramps, myoclonus, and hemiballismus, were also observed during the course of the follow-up. While he was able to perform basic functions like eating, climbing stairs, walking, and writing with the aid of levodopa and trihexyphenidyl treatment, his clinical status gradually deteriorated secondary to progressive generalized dystonia in the 4-year follow-up. Deep brain stimulation has been shown to be effective in several patients which could be the next preferred treatment for the patient.

Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing

A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the <i>MUTYH</i>, <i>BRCA2</i>, and <i>CHEK2</i> genes. Nine novel pathogenic/likely pathogenic variants were identified in <i>BRCA1</i>, <i>BRCA2</i>, <i>GALNT12</i>, <i>ATM</i>, <i>MLH1</i>, <i>MSH2</i>, <i>APC</i>, and <i>KIT</i> genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.

Xq21.1q21.31 Duplication in Two Male Siblings

Despite the increased use of array comparative genomic hybridisation, duplications of Xq remain rarely reported in the literature. Xq21.1q21.31 duplication has previously been reported only once in a boy with features of Prader Willi syndrome (PWS). We report 2 malesiblings with maternally inherited duplication of Xq21.1q21.31 who demonstrate a variable phenotype. The proband has Prader Willi-like features such as global developmental delay, autism, obesity, short hands, and small genitalia with a history of food seeking behaviour, while his younger brother has isolated speech delay with some autistic features under evaluation. Both siblings have features such as bitemporal narrowing and small hands. It is therefore likely that the phenotype of duplications in this region is broader than PWS phenocopy, and further cases would be required to elucidate this.

An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment

Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G&#x3e;C (p.Gly309Arg) variant and a heterozygous c.1129G&#x3e;A (p.Val377Ile) mutation in the <i>MVK</i> gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.