Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes.

Familial myelodysplastic syndromes: a review of the literature.

To the Editor : For years, human genotype–phenotype studies have suggested DYRK1A (MIM 600855) as a candidate gene for microcephaly and mental retardation (MR) (1–3). These findings have been supported by various animal models such as Drosophila and mice (4, 5). DYRK1A is a member of the dual-specificity tyrosine phosphorylationregulated kinase (DYRK) family and participates in various cellular processes. It is a highly conserved gene located in the Down Syndrome Critical Region, a part on chromosome 21 that is responsible for the majority of phenotypic features in Down syndrome (6, 7). Convincing evidence for a brain developmental function of DYRK1A in humans was recently provided by a report on two mentally retarded individuals with a balanced translocation truncating this gene (8). However, so far, no pure DYRK1A deletions in humans have been reported. In this study, we investigated whether smaller copy number variations (CNVs), below the routine diagnostic threshold set at 150 kb, may be present at the DYRK1A locus. Therefore, the intensity log2 ratios of all single nucleotide polymorphism (SNP) probes located within and surrounding the DYRK1A gene (37,647,772–37,813,457 bp) were studied in 3009 mentally retarded individuals, in whom no pathogenic CNVs (>150 kb) were detected during routine diagnostic 250K SNP array analysis (Affymetrix Inc., Santa Clara, CA) (9). Patients in which at least four consecutive SNP probes showed an abnormal log2 ratio (<−0.2 or >0.25) were considered to be candidates for having a DYRK1A deletion or duplication. Of the 16 candidate aberrations fulfilling this criterion one deletion could be confirmed by quantitative polymerase chain reaction (qPCR, Supporting information, Table S1) and was shown to be de novo (Fig. 1b). A high-resolution NimbleGen hg18 chromosome 21 specific 385K array subsequently revealed that the deletion had a size of 52 kb (37,796,500–37,849,000 bp) and deleted the last three exons of DYRK1A (Fig. 1c). The female with the DYRK1A deletion was born with a length of 48 cm (−2 SD), weight of 3195 g (−1 SD) and a head circumference of 33 cm (<−2 SD). From birth onward, she had feeding problems with failure to thrive and non-fluent motoric movements and hypoactivity were noted. During infancy she regularly had febrile seizures. At 24 years of age, a cerebral magnetic resonance imaging (MRI) showed a mild atrophic brain and medulla without structural congenital anomalies. At 33 years of age, she had severe MR without speech and showed anxious autistic behavior. She walked with a stiff motoric gait and jerky movements. She had a slender posture with a length of 161.5 cm (−1.5 SD) and an occipitofrontal circumference (OFC) of 50.5 cm (−3 SD). Facial dysmorphisms included bitemporal narrowing, deep-set eyes, large simple ears and a pointed nasal tip. In addition, she had eczema, hypoplasia of breasts, hallux valgus of feet and an irregular implant of toes. Several features in this patient, such as severe developmental delay, growth retardation, nonfluent motoric movements, microcephaly in the absence of structural brain anomalies, hypoactivity and anxious behavior, show a striking similarity with features observed in different animal models with mutated DYRK1A. The Drosophila ortholog of DYRK1A is the minibrain (mnb) gene (5). The mnb gene plays an important role in regulating the number of distinct neuronal cell types. These mutants are slightly smaller in size and show behavior problems, characterized by poor visual pattern fixation, reduced walking activity and speed, and poor odor discrimination (5). Dyrk1A+/− mice show preand postnatal growth retardation, developmental delay, specific motor and learning deficits, visual impairment, behavioral defects and increased anxiety (4, 10–13). Brains of mutant mnb flies and Dyrk1A+/− mice are greatly reduced in size, although the neuronal architecture remains unchanged. On the basis of human genotype–phenotype studies of partial monosomies 21, DYRK1A has

Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly

DYRK1A and cognition: A lifelong relationship

TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt–Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.

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Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

/pdf/dyrk1a-haploinsufficiency-causes-a-new-recognizable-syndrome-dxky5iqo6x.pdf

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

The concept of the Down syndrome critical region implies the existence of several dosage-sensitive genes that result in an abnormal phenotype when duplicated. Among the genes in the presumed Down syndrome critical region, DYRK1A and SIM2 are thought to be particularly important because of their critical roles in the development of the central nervous system in model organisms. Considering that regulatory imbalances resulting in an altered amount of expression from crucial target genes tend to produce phenotypic effects in both monosomics and trisomics, haploinsufficiency for the Down syndrome critical region is expected to be associated with an abnormal phenotype. We report on a patient with severe microcephaly, a developmental delay, hypospadias, and corneal opacity who had a microdeletion spanning the Down syndrome critical region, including DYRK1A and SIM2. He presented with intrauterine growth retardation, hypospadias, corneal clouding, arched eyebrows, upslanting and narrow palpebral fissures, bifid uvula, prominent nasal root, short columella, prominent central incisors, pegged shaped teeth, retrognathia, hypoplastic nipples, and severe developmental delay. His G-banded karyotype was normal, but array comparative genomic hybridization showed a de novo deletion of 3.97 Mb at chromosome 21q22. The extreme degree of microcephaly in this patient may be ascribed to the haploinsufficiency of DYRK1A, since brain size is severely reduced in heterozygotes for the Dyrk1a null mutation in mice.

Microdeletion of the Down syndrome critical region at 21q22.

Tissue-Limited Ring Chromosome 18 Mosaicism as a Cause of Pitt–Hopkins Syndrome Toshiki Takenouchi, Tatsuhiko Yagihashi, Hiroyuki Tsuchiya, Chiharu Torii, Kumiko Hayashi, Rika Kosaki, Shinji Saitoh, Takao Takahashi, and Kenjiro Kosaki* Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan Center for Clinical Research, Keio University School of Medicine, Tokyo, Japan Department of Pediatrics, Tachikawa Kyosai Hospital, Tokyo, Japan Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan Mitsubishi Chemical Medience Corporation, Tokyo, Japan Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Kumiko Hayashi

Papers

Microdeletion of the Down syndrome critical region at 21q22.

Tissue-limited ring chromosome 18 mosaicism as a cause of Pitt-Hopkins syndrome.