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Blake C Ballif,
Jill A Rosenfeld,
Ryan Traylor,
Aaron Theisen,
Patricia I Bader,
Roger L Ladda,
Susan L Sell,
Michelle Steinraths,
Urvashi Surti,
Marianne McGuire, [......],
Arthur S Aylsworth,
J S Bamforth,
Deepti Babu, Dmitriy M Niyazov,
J Britt Ravnan,
Roger A Schultz,
Allen N Lamb,
Beth S Torchia,
Bassem A Bejjani,
Lisa G Shaffer
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ABSTRACT: Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.
Human Genetics 07/2011; 131(1):145-56. · 5.07 Impact Factor
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Deepika D'Cunha Burkardt,
Jill A Rosenfeld,
Maria L Helgeson,
Brad Angle,
Valerie Banks,
Wendy E Smith,
Karen W Gripp,
Jessica Moline,
Rocio T Moran, Dmitriy M Niyazov,
Cathy A Stevens,
Elaine Zackai,
Robert Roger Lebel,
Douglas G Ashley,
Nancy Kramer,
Ralph S Lachman,
John M Graham
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ABSTRACT: Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.
American Journal of Medical Genetics Part A 06/2011; 155A(6):1336-51. · 2.39 Impact Factor
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ABSTRACT: Subtelomeric imbalances have been implicated in developmental delay and mental retardation (MR) and described for most chromosomes. This study reports the first detailed description of two individuals with de novo 12q subtelomere deletions and high-resolution mapping of their deletion size with oligonucleotide array CGH for genotype/phenotype comparisons. Patient 1 is an 8-year-old male with borderline mild MR, food-seeking behavior, obesity, no significant dysmorphic facial features, abnormal hair whorl pattern, brachydactyly and mild clinodactyly. Patient 2 is a 12-year-old male with mild MR, food-seeking behavior, obesity, short stature, mild dysmorphic facial features, multicystic kidney and unilateral cryptorchidism. Both patients share a deleted region of approximately 1.6 Mb, including 14 known genes, which perhaps contributed to their similar phenotypes. However, Patient 2 has more severe MR and organ system involvement, possibly due to the larger deletion size ( approximately 4.5 Mb) including an additional eight genes, although it is difficult to make phenotype/genotype correlations based on only two patients. Due to the relatively mild presentation of both of our patients, we propose that a proportion of individuals with subtelomeric imbalances may go undetected and therefore, recommend subtelomeric studies be carried out for cases of unexplained mild MR or isolated learning disability (LD) with behavioral problems in the absence of major dysmorphic features or birth defects. In addition, 12q subtelomeric deletions should be considered in the differential diagnosis of patients presenting with food-seeking behavior and resultant obesity, as well as those referred to rule out Prader-Willi syndrome.
American Journal of Medical Genetics Part A 12/2007; 143A(22):2700-5. · 2.39 Impact Factor
