4q21 microdeletion in a patient with epilepsy and brain malformations

Yano, Sho; Mcnamara, M. Eileen; Halbach, Sara; Waggoner, Darrel

doi:10.1002/ajmg.a.36910

Cited by 3 publications

(3 citation statements)

References 18 publications

(22 reference statements)

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“…PRKG2 is expressed at high levels in the brain (McCall et al, 2011) and the homozygous knock-out of the mouse ortholog, Prkg2, causes abnormal bone ossification, resulting in abnormal cranium morphology and shorter limbs (Pfeifer et al, 1996). Therefore, PRKG2 haploinsufficiency may account for growth restriction abnormalities observed in 4q21.22 microdeletion syndrome (Bhoj et al, 2013;Bonnet et al, 2010;Yano et al, 2015). COPS4 encodes a ubiquitously expressed subunit of the conserved COP9 signalosome, a conserved protein complex that regulates multiple signaling pathways (Min et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

Zarrei

Merico

Kellam

et al. 2017

American J of Med Genetics Pt A

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We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.

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Section: Discussionmentioning

confidence: 99%

“…for additional information Waggoner, 2015). Cerebral palsy has also been observed in some individuals with 4q21.22 syndrome (Bhoj et al, 2013).…”

mentioning

confidence: 99%

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

Zarrei

Merico

Kellam

et al. 2017

American J of Med Genetics Pt A

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“…The great variability and severity of congenital malformations and disorders related to the 4q deletion have been reported to affect different organs and in most cases the anomalies are complexes with various organs and body areas involved in the associations. Anomalies have been reported affecting the brain (ventriculomegaly, cortical atrophy and prominent ventricles, large occipital encephalocele) [12][13][14], eyes (bilateral hypermetropia, pigmentary retinal degeneration, microphthalmia) [15][16][17][18], cleft palate and Pierre Robin syndrome [3,5,7,[19][20][21], heart (enlarged right atrium and ventricle, small atrial septal defect, abnormal structure and function of both ventricles and double inferior vena cava, coarctation of the aorta and interventricular communication, both valvar pulmonic stenosis, cor triatriatum) [3,8,[22][23][24], kidneys (duplicated left intrarenal collecting system, polycystic kidney, bilateral extrarenal pelvis dysplastic cystic kidneys) [3, 9, 24-26], genital defects [27], limb development disorder (irregularity of the outline of the distal phalanx of the 4th digit, rudimentary left thumb with absence of right thumb, bilateral absence of ulna) [28][29][30][31]. Craniofacial dysmorphism has frequently been reported with signs that are not speci cally diagnostic [32][33][34][35][36], as well cognitive involvement [17,[37][38][39][40][41], de cit of growth [25,34] and epileptic seizures [22,…”

Section: Discussionmentioning

confidence: 99%

Clinical comparison between terminal and interstitial 4q deletion in two unrelated children

Pappalardo

Lubrano

Verrotti

et al. 2022

Preprint

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Background. The term “4q deletion syndrome” is defined to include two different regions: an interstitial sequence deleted from the centromere to 4q31 and a terminal deletion from 4q31 to 4qter. Objective. To compare clinical similarities and differences between two unrelated children of the same age observed during the same time period by the same Center, one presenting with a 4q interstitial deletion, the other with a terminal 4q deletion. The clinical manifestations were compared. Cases Presentation. Clinical manifestations observed in two children from the infancy to the age of 7 years included: craniofacial features, pre- and postnatal growth failure, and speech and developmental delay. Case 1 showed a terminal 4q deletion of about 329.6 Kb extending from 164.703.186 to 165.032.803 nt, Case 2 displayed an interstitial 4q deletion 600.3 Kb long spanning from 71.655.407 to 78.016.622 nt. Results. Growth retardation, craniofacial features, mild developmental delay and notable speech delay. were reported in both the probands. Precocious crowded dentition was observed in Case 1 and an accessory spleen in Case 2. Conclusion. Patients with 4q deletion syndrome although sharing main features, exhibited varying clinical manifestations depending on the area and location of the deletion. Similarity and diversity reported for the probands are analyzed. An extensive review of the 4q deletion syndrome is reported.

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A de novo microtriplication at 4q21.21‐q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech

Lebedev

Назаренко

Skryabin

et al. 2016

American J of Med Genetics Pt A

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The widespread application of array comparative genomic hybridization (aCGH) has provided new insights into the clinical significance of copy number variations (CNVs) in the human genome. Many microdeletion syndromes have recently been linked to corresponding reciprocal microduplication syndromes related to CNVs in the same chromosomal regions. However, the extent of CNVs may not be restricted to only microduplications but may also include microtriplications or even quadruplications. 4q21 microdeletion syndrome is one of these recently described syndromes. The phenotype includes growth restriction, neonatal hypotonia, severe developmental delay, absent or delayed speech, and distinct facial features. The minimal critical deleted region, which is 1.3 Mb in size, contains the PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1 genes. Here, we report a 5.4-year-old girl with developmental delay, absence of speech, muscular hypertension, macrocephaly, a broad forehead, frontal bossing, relatively elongated extremities, a vascular malignant hemangioma in anamnesis, and elongated sigmoid colon. aCGH revealed a microtriplication at 4q21.21-q21.22 that was 1.61 Mb in size. This de novo microtriplication included nine genes (BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, LINC00575, and SCD5) and overlapped with the minimal critical region for 4q21 microdeletion syndrome. Some clinical features of the patient were similar to those of 4q21 microdeletion (macrocephaly, frontal bossing, developmental delay, absence of speech, and anxiety), whereas others were mirrored (elongated extremities and muscular hypertension). The first identified case of a de novo microtriplication at 4q21.21-q21.22 emphasizes the clinical significance of CNVs at 4q21 for patients with developmental delay and absence of speech. © 2016 Wiley Periodicals, Inc.

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4q21 microdeletion in a patient with epilepsy and brain malformations

Cited by 3 publications

References 18 publications

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

Clinical comparison between terminal and interstitial 4q deletion in two unrelated children

A de novo microtriplication at 4q21.21‐q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech

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