Madeleine Fannemel

Update on Kleefstra Syndrome

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

SCA27 caused by a chromosome translocation: further delineation of the phenotype

We report of a spinocerebellar ataxia (SCA)27 in a daughter and her mother whose karyotype is 46, XX t(5;13)(q31.2;q33.1). The translocation breakpoint is identical in both patients, disrupting the gene-encoding fibroblast growth factor 14 isoform b (FGF14-1b). Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation. FGF14-1b is the predominant isoform in brain, where it interacts with the voltage gated Na channel. Fgf14−/− mice develop ataxia and paroxysmal dyskinesia and have cognitive deficits. One missense and one non-sense mutation in FGF14 have previously been linked to SCA27. Truncation of one allele in our patients suggests that haploinsuffiency of FGF14 can cause SCA27.

A translocation between Xq21.33 and 22q13.33 causes an intragenic SHANK3 deletion in a woman with Phelan–McDermid syndrome and hypergonadotropic hypogonadism

Chromosome 22q13 monosomy has been described as a contiguous gene syndrome. Localized in the critical region, SHANK3 is likely to play a key role in the expression of the clinical phenotype. SHANK3 mutations have also been reported in autistic patients without a syndromic phenotype. We report on a 20‐year‐old woman with mental retardation carrying a de novo translocation between chromosome Xq21.33 and 22q13.33, associated with a duplication on Xq21.33 and deletion on 22q13.33. As a child her development was characterized by disturbed social interaction, stereotypic hand movements and ritualistic behavior and she was considered at one time to have autistic features. All these traits match the 22q13 deletion syndrome (Phelan–McDermid syndrome, OMIM 606232), likely due to the deletion overlapping the last two exons of the SHANK3 gene. Our patient harbors the smallest and most distal SHANK3 deletion described to date, yet resulting in the full spectrum of the Phelan–McDermid syndrome. In addition, she has hypergonadotropic hypogonadism with low estrogen level, high FSH level, and irregular menstruation. Intriguingly, chromosome translocations affecting the chromosome band Xq21 can result in premature ovarian failure.

Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability

MEIS2 is a homeodomain‐containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326–1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.

1.5Mb deletion of chromosome 4p16.3 associated with postnatal growth delay, psychomotor impairment, epilepsy, impulsive behavior and asynchronous skeletal development.

Several Wolf-Hirschhorn syndrome patients have been studied, mouse models for a few candidate genes have been constructed and two WHS critical regions have been postulated, but the molecular basis of the syndrome remains poorly understood. Single gene contributions to phenotypes of microdeletion syndromes have often been based on the study of patients carrying small, atypical deletions. We report a 5-year-old girl harboring an atypical 1.5Mb del4p16.3 and review seven previously published patients carrying a similar deletion. They show a variable clinical presentation and the only consistent feature is post-natal growth delay. However, four of eight patients carry a ring (4), and ring chromosomes in general are associated with growth deficiency. The Greek helmet profile is absent, although a trend towards common dysmorphic features exists. Variable expressivity and incomplete penetrance might play a role in WHS, resulting in difficult clinical diagnosis and challenge in understanding of the genotype/phenotype correlation.

Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability.

BackgroundNineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1–17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes.Methods and resultsWe describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1–3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1–4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1–3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1–3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.ConclusionsPatients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Hyperphagia, mild developmental delay but apparently no structural brain anomalies in a boy without SOX3 expression.

The transcription factor SOX3 is widely expressed in early vertebrate brain development. In humans, duplication of SOX3 and polyalanine expansions at its C‐terminus may cause intellectual disability and hypopituitarism. Sox3 knock‐out mice show a variable phenotype including structural and functional anomalies affecting the branchial arches and midline cerebral structures such as the optic chiasm and the hypothalamo‐pituitary axis. SOX3 is claimed to be required in normal brain development and function in mice and humans, as well as in pituitary and craniofacial development. We report on an 8‐year‐old boy with a 2.1 Mb deletion in Xq27.1q27.2, which was found to be inherited from his healthy mother. To our knowledge, this is the smallest deletion including the entire SOX3 gene in a male reported to date. He is mildly intellectually disabled with language delay, dysarthria, behavior problems, minor facial anomalies, and hyperphagia. Hormone levels including growth, adrenocorticotropic and thyroid stimulating hormones are normal. Magnetic resonance imaging (MRI) at age 6 years showed no obvious brain anomalies. Genetic redundancy between the three members of the B1 subfamily of SOX proteins during early human brain development likely explains the apparently normal development of brain structures in our patient who is nullisomic for SOX3.

A de novo 163 kb interstitial 1q44 microdeletion in a boy with thin corpus callosum, psychomotor delay and seizures

The 1q44 deletion syndrome has shown to be a recognizable phenotype with developmental delay, short stature and corpus callosum abnormalities as relatively consistent features. However, the disorder is still clinically heterogeneous and a genotype-phenotype correlation has been challenging to establish. In particular, a delineation of a critical region for the corpus callosum development has turned out to be difficult, and many candidate genes have been proposed. We present here a patient boy with a clinical picture of the 1q44 deletion syndrome, including a thin corpus callosum, and a small de novo 1q44 deletion. The deletion spans a maximum of 163 kb, a region which only contains the two genes FAM36A and HNRNPU. This finding supports the previously suggested hypothesis that the HNRNPU is an essential gene to the development of corpus callosum. However, as patients with deletions outside this interval also have been reported to have corpus callosum abnormalities, other mechanisms are probably also involved. We also identified two conserved non-coding regions in the deleted region of the patient, and speculate that also other elements interfere with the complex interplay and spatiotemporal gene expression during embryonic development.

A 1 Mb de novo deletion within 11q13.1q13.2 in a boy with mild intellectual disability and minor dysmorphic features

We report a 11 year old male patient ascertained for mild intellectual disability and minor dysmorphic features, carrying a 1 Mb de novo deletion on chromosome 11q13.1q13.2 detected by aCGH. This is the first report of a deletion in this region in a patient presenting with intellectual impairment and mild dysmorphic traits. The 1 Mb deleted area encompasses 47 RefSeq genes, including Cornichon homologue 2 (CNIH2), Cofilin-1 (CFL1) and neuronal PAS domain-containing protein 4 (NPAS4), which are highly expressed in the central nervous system. Knockout of the CNIH2 and CFL1 orthologues in animals results in migration disturbances, while low or no expression of Npas4 in mice results in impairment of memory and learning. These three genes have previously been suggested as candidate genes for neurological disorders.

Haploinsufficiency of ANO6, NELL2 and DBX2 in a boy with intellectual disability and growth delay

We report on a 10‐year‐old‐boy presenting with moderate intellectual disability (ID), impaired motor skills, hypotonia, growth delay, minor anomalies, misaligned teeth, pectus excavatum, small hands and feet, widely spaced nipples, and a 1.13 Mb de novo deletion on HSA12q12 (chr12:44,830,147‐45,964,945 bp, hg19), deleting ANO6, NELL2, and DBX2 and the pseudogenes PLEKHA8P1 and RACGAP1P. We suggest DBX2 and NELL2 as disease‐causing genes and their haploinsufficiency to be involved in the psychomotor delay in the patient. DBX2 encodes a homeobox protein, highly expressed during neuronal development and regulating differentiation of interneurons in brain and spinal cord. NELL2 is expressed in most of the central and peripheral nervous system, with highest expression in hippocampus and cerebellum, maximizing during neuronal differentiation. The deletion in our patient is the smallest in HSA12q12 reported to date, and it is included in the deletion carried by four previously reported patients. The clinical presentation of these patients points to the recurrence of the following manifestation, possibly delineating a 12q12 deletion syndrome phenotype: moderate to severe developmental/intellectual delay, hypotonia, postnatal growth retardation, skeletal and dental anomalies, minor facial anomalies including strabismus, down slanting palpebral fissures, and large/low‐set ears.