Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation.

A male child, born from consanguineous parents and having intellectual disability, short stature, dysmorphic facial features, synpolydactyly, and cardiac malformations is reported. Chromosomal microarray analysis showed that the patient presents with an 8p23.1 homozygous deletion, containing the microRNA miR-4660, the exoribonuclease 1 (ERI1), and malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) genes. The microRNA miR-4660 has no known function. MFHAS1 is an immunomodulatory protein involved in Toll-like receptor signaling, erythropoiesis, and cancer. ERI1 is a ribonuclease involved in RNA metabolism and is required for the correct patterning of the skeleton by defining the HOXC8 expression. We discuss the involvement of these deleted genes to the patient's features and highlight differential diagnoses with syndromes implicating limb extremity abnormalities such as synpolydactyly, including the monosomy 8p.

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

BACKGROUND: KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS). METHODS: Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants. RESULTS: Whole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G > A in KCNH1, c.2131 T > C in STK36, and c.726C > A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect. CONCLUSIONS: Our findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.

10q26.1 Microdeletion: Redefining the critical regions for microcephaly and genital anomalies.

Distal 10q deletion syndrome is a well-characterized chromosomal disorder consisting of neurodevelopmental impairment, facial dysmorphism, cardiac malformations, genital and urinary tract defects, as well as digital anomalies. Patients with interstitial deletions involving band 10q26.1 present a phenotype similar to the ones with the distal 10q deletion syndrome, which led to the definition of a causal 600 kb smallest region of overlap (SRO). In this report, we describe a male patient with an interstitial 4.5 Mb deletion involving exclusively the 10q26.1 segment. He had growth and psychomotor retardation, microcephaly, flat feet, micropenis, and cryptorchidism. The patient's deleted region does not overlap the 10q SRO. We reviewed the clinical phenotype of patients with similar deletions and suggest the presence of two new SROs, one associated with microcephaly, growth and psychomotor retardation, and the other associated to genital anomalies. Interestingly, we narrowed those regions to segments encompassing five and two genes, respectively. FGFR2, NSMCE4A, and ATE1 were suggested as candidates for facial dysmorphism, growth cessation, and heart defects, respectively. WDR11 was linked to idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Its haploinsufficiency could play a crucial role in the genital anomalies of these patients.

Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.

Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability.

BACKGROUND: The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID). RESULTS: We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT-PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss. CONCLUSIONS: The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.

Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients.

BACKGROUND: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. RESULTS: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. CONCLUSION: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs.

Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations.

BACKGROUND: Heterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described. SUBJECT: A 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present. METHODS: Auxological and endocrinological profiles were measured. All coding regions of the IGF1R gene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts. RESULTS: IGF1 level was elevated at 950NG/ML (+7 S.D.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. sequencing of the IGF1R gene led to the identification of a homozygous variation in exon 2: c.119G>T (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation. CONCLUSION: The homozygous mutation of the IGF1R is associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.