Contiguous Deletion Syndrome Research Articles

Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption?

BackgroundMesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation.Case presentationWe present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced “de novo” reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints.ConclusionsThe identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1.

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

Background Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex.Aims To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex.Study designRetrospective, cross-sectional study.Methods Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines.Results In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene.Conclusion The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.

Prenatal diagnosis of Jacobsen syndrome with cystic hygroma

Jacobsen syndrome (JBS) is a rare, contiguous genetic deletion syndrome caused by partial deletion of chromosome 11q. It is difficult to diagnose JBS by ultrasonography during the prenatal period because it has atypical clinical findings. Although nuchal thickening is associated with JBS, cystic hygroma has not been previously reported in conjunction with this syndrome. We describe the first prenatal diagnosis of JBS with cystic hygroma, which was clinically diagnosed at 13 weeks gestation in a Japanese woman, although it had not been detectable at the 11th week of gestation. In addition, a single ventricle fetal heart defect was suspected. Amniocentesis was performed, and G-banded karyotype evaluation revealed 46,XX,del(11)(q23), which is consistent with JBS. Cystic hygroma and congenital heart malformation have been reported to be associated with chromosomal anomalies. The present case indicates that a fetal cystic hygroma without increased nuchal thickness might be associated with JBS.

Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology.

Autism spectrum disorder (ASD) is a set of neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. Parental consanguinity may lead to higher risk of ASD and to more severe clinical presentations in the offspring. Studies of ASD families with high inbreeding enable the identification of inherited variants of this disorder particularly those with an autosomal recessive pattern of inheritance. In our study, using copy number variants (CNV) analysis, we identified a rare homozygous deletion in 2p11.2 region that affects ELMOD3, CAPG, and SH2D6 genes in a boy with ASD, intellectual disability (ID), and hearing impairment (HI). This deletion may reveal a new contiguous deletion syndrome in which ELMOD3, known to be implicated in autosomal recessive deafness underlies the HI of the proband and CAPG, member of actin regulatory proteins involved in cytoskeletal dynamic, an important function for brain development and activity, underlies the ASD/ID phenotype. A possible contribution of SH2D6 gene, as a part of a chimeric gene, to the clinical presentation of the patient is discussed. Our result supports the implication of ELMOD3 in hearing loss and highlights the potential clinical relevance of 2p11.2 deletion in autism and/or intellectual disability.

Atypical Hypotonia-Cystinuria a New Case: Genotype-Phenotype, Description

“Hypotonia-cystinuria syndrome” (HCS) and “the 2p21 deletion syndrome” are two recessive contiguous gene deletion syndromes associated with cystinuria. The deletions differ in size and number of genes involved. HCS is characterized by hypotonia, failure to thrive, severe growth retardation, growth hormone deficiency, characteristic facial dysmorphy and cystinuria. In addition to mental retardation and respiratory chain complex deficiency, the 2p21 deletion syndrome presents HCS features. In HCS, SLC3A1 and PREPL genes are disrupted, while in the 2p21 deletion syndrome two additional genes (C2orf34 and PM1B) are deleted. Mutations in SLC3A1 are known to cause cystinuria. The extended phenotypes are attributed to PREPL and C2orf34 PM1B deletions. While HCS is described in 19 families, 2p21 syndrome is only in one Bedouin family. An intermediate phenotype, resulting from deletion of SLC3A1, PREPL and C2orf34 has been reported twice and is known as “atypical HCS”. We will describe a new case of “atypical HCS” and its genotype-phenotype correlation. Array-CGH evidenced a homozygote microdeletion in chromosome 2p21 partially including genes SLC3A1 and CAMKMT and complete inclusion of the PREPL gene. Both parents showed the same deletion in the heterozygous state. In contiguous deletion syndromes, characterization of the different deletions is crucial for precise genotype-phenotype correlation and to understand the role of each gene.

Neurodegenerative changes detected by neuroimaging in a patient with contiguous X-chromosome deletion syndrome encompassing BTK and TIMM8A genes.

IntroductionIn this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness.Material and methodsFor neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion.ResultsThe first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient’s DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome’s loci Xq22.1.ConclusionsWe diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.

Improving molecular diagnosis of aniridia and WAGR syndrome using customized targeted array-based CGH.

Chromosomal deletions at 11p13 are a frequent cause of congenital Aniridia, a rare pan-ocular genetic disease, and of WAGR syndrome, accounting up to 30% of cases. First-tier genetic testing for newborn with aniridia, to detect 11p13 rearrangements, includes Multiplex Ligation-dependent Probe Amplification (MLPA) and karyotyping. However, neither of these approaches allow obtaining a complete picture of the high complexity of chromosomal deletions and breakpoints in aniridia. Here, we report the development and validation of a customized targeted array-based comparative genomic hybridization, so called WAGR-array, for comprehensive high-resolution analysis of CNV in the WAGR locus. Our approach increased the detection rate in a Spanish cohort of 38 patients with aniridia, WAGR syndrome and other related ocular malformations, allowing to characterize four undiagnosed aniridia cases, and to confirm MLPA findings in four additional patients. For all patients, breakpoints were accurately established and a contiguous deletion syndrome, involving a large number of genes, was identified in three patients. Moreover, we identified novel microdeletions affecting 3' PAX6 regulatory regions in three families with isolated aniridia. This tool represents a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a more accurate CNVs detection, as well as a better delineation of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns and those without defects in PAX6 after diagnostic screening.

X-linked elliptocytosis with impaired growth is related to mutated AMMECR1

In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss. Recently, mutations in AMMECR1 were reported in two maternal half-brothers, presenting with nephrocalcinosis, midface hypoplasia and, in one of the siblings, deafness and elliptocytosis. AMMECR1 gene is localized in the critical region of contiguous deletion syndrome on Xq22.3 implicated in Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME complex). Interestingly, alternative splicing of exon 2, the same exon harboring the truncating mutation, was observed in the proband and in his unaffected mother. Alternative splicing of this exon is predicted to lead to an in-frame deletion. We provide further evidence that mutated AMMECR1 gene is responsible for this clinically recognizable X-linked condition with variable expressivity.

Genomic copy number alterations in non-syndromic hearing loss.

Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment.

Two Novel Gross Deletions of TSC2 in Malaysian Patients with Tuberous Sclerosis Complex and TSC2/PKD1 Contiguous Deletion Syndrome

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder affecting multiple organs. Tuberous sclerosis complex is caused by mutation in either one of the two disease-causing genes, TSC1 or TSC2, encoding for hamartin and tuberin, respectively. TSC2/PKD1 contiguous gene deletion syndrome is a very rare condition due to deletion involving both TSC2 and PKD1 genes. Tuberous sclerosis complex cannot be easily diagnosed since there is no pathognomonic feature, although there are consensus diagnostic criteria for that. Mutation analysis is useful and plays important roles. We report here two novel gross deletions of TSC2 gene in Malay patients with tuberous sclerosis complex and TSC2/PKD1 contiguous gene deletion syndrome, respectively.

Genetic basis of hyperlysinemia

BackgroundHyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia.MethodsWe collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features.ResultsWe found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1.ConclusionsHyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.

Contiguous ABCD1 DXS1357E deletion syndrome: Report of an autopsy case

Contiguous ABCD1 DXS1357E deletion syndrome (CADDS) is a contiguous deletion syndrome involving the ABCD1 and DXS1357E/BAP31 genes on Xq28. Although ABCD1 is responsible for X-linked adrenoleukodystrophy (X-ALD), its phenotype differs from that of CADDS, which manifests with many features of Zellweger syndrome (ZS), including severe growth and developmental retardation, liver dysfunction, cholestasis and early infantile death. We report here the fourth case of CADDS, in which a boy had dysmorphic features, including a flat orbital edge, hypoplastic nose, micrognathia, inguinal hernia, micropenis, cryptorchidism and club feet, all of which are shared by ZS. The patient achieved no developmental milestones and died of pneumonia at 8 months. Biochemical studies demonstrated abnormal metabolism of very long chain fatty acids, which was higher than that seen in X-ALD. Immunocytochemistry and Western blot showed the absence of ALD protein (ALDP) despite the presence of other peroxisomal proteins. Pathological studies disclosed a small brain with hypomyelination and secondary hypoxic-ischemic changes. Neuronal heterotopia in the white matter and leptomeningeal glioneuronal heterotopia indicated a neuronal migration disorder. The liver showed fibrosis and cholestasis. The thymus and adrenal glands were hypoplastic. Array comparative genomic hybridization (CGH) analysis suggested that the deletion was a genomic rearrangement in the 90-kb span starting in DXS1357E/BACP31 exon 4 and included ABCD1, PLXNB3, SRPK3, IDH3G and SSR4, ending in PDZD4 exon 8. Thus, the absence of ALDP, when combined with defects in the B-cell antigen receptor associated protein 31 (BAP31) and other factors, severely affects VLCFA metabolism on peroxisomal functions and produces ZS-like pathology.

1.9 Mb microdeletion of 21q22.11 within Braddock–Carey contiguous gene deletion syndrome region: Dissecting the phenotype

Braddock-Carey syndrome is characterized by Pierre Robin sequence, agenesis of the corpus callosum, facial dysmorphisms, developmental delay, and congenital thrombocytopenia. Recently, Braddock-Carey syndrome was demonstrated to be caused by chromosomal microdeletion in 21q22 including the RUNX1 gene, whose haploinsufficiency is responsible for thrombocytopenia phenotype. Therefore, the syndrome has emerged as a contiguous gene deletion syndrome. Here, we describe an infant with Pierre Robin sequence, facial anomalies, congenital heart defects, hypotonia, and the absence of thrombocytopenia, who was found to have a 1.9 Mb microdeletion within the Braddock-Carey contiguous deletion syndrome region. This deletion spares the RUNX1 gene, narrowing the genomic region responsible for a part of the Braddock-Carey syndrome phenotype. Further studies are awaited to understand the role of the genes located within 21q22 in the pathogenesis of Braddock-Carey syndrome.

Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

Patients with X-linked agammaglobulinemia (XLA) can present with sensorineural deafness. This can result from a gross deletion that not only involved the Bruton's tyrosine kinase (BTK) gene, but also TIMM8A, mutations in which underlie the Mohr-Tranebjærg syndrome (MTS). We analyzed the genomic break points observed in three XLA-MTS patients and compared these with deletions break points from XLA patients. Patient 1 had a 63-kb deletion with break points in intron 15 of BTK and 4 kb upstream of TAF7L. Patients 2 and 3 had 149.7 and 196 kb deletions comprising BTK, TIMM8A, TAF7L and DRP2. The break points in patients 1 and 3 were located in Alu and endogenous retrovirus (ERV) repeats, whereas the break points in patient 2 did not show involvement of transposable elements. Comparison of gross deletion sizes and involvement of transposable elements in XLA and XLA-MTS patients from the literature showed preferential involvement of Alu elements in smaller deletions (<10 kb). These results show further insights into the molecular mechanisms underlying gross deletions in patients with primary immunodeficiency.

The Xp contiguous deletion syndrome and autism

Xp22 nullisomy in males causes a phenotype consistent with the loss of one or more of the genes located in this chromosomal region. Females with similar Xp deletions rarely manifest the same phenotype. Here we describe a 10-year-old girl with a de novo interstitial deletion encompassing Xp22.2p22.32 who presented with autism, moderate mental retardation, and some dysmorphic features. The deletion was delineated by FISH and STR analyses, and the breakpoints were determined using the Agilent 244 K oligonucleotide array. We found that the 5.5 Mb deletion is located on the paternal X chromosome and encompasses 18 genes. Further molecular and cytogenetic analyses showed unfavorable skewing of X-inactivation of the maternal (intact) chromosome. The phenotype of our patient was compared with previously reported female patients with deletions encompassing the same chromosomal region. We discuss the potential role of the genes in the deleted region and X chromosome inactivation in the pathogenesis of the phenotypic abnormalities seen in our patient. Our findings suggest that the severity and the variability of the clinical findings are determined by the size and the parental origin of the deletions as well as the X-inactivation status.

Contiguous X-chromosome Deletion Syndrome Encompassing the BTK, TIMM8A, TAF7L, and DRP2 Genes

X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The neurologic symptoms suggested the diagnosis of Mohr-Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of the deletion.

Comparing ADHD in Velocardiofacial Syndrome to Idiopathic ADHD

Objective: Background: Children with velocardiofacial syndrome (VCFS), a contiguous deletion syndrome, have an increased prevalence of attention deficit/hyperactivity disorder (ADHD). Method: The authors compared youth with VCFS+ADHD (from the SUNY Upstate VCFS Research Program) to those with ADHD but not VCFS (from the Massachusetts General Hospital Longitudinal Family Studies of ADHD). Results: Children with VCFS+ADHD were more likely to be diagnosed with the inattentive subtype and differed from idiopathic ADHD in the frequency of several inattentive symptoms that appear linked to general cognitive functioning. After controlling for IQ differences, parents of children with VCFS+ADHD endorsed more thought and social problems on a rating checklist. Patterns of comorbidity also differed between the two groups of children with ADHD: Children with idiopathic ADHD had higher rates of comorbid major depression and disruptive behavior disorders. Conclusion: Children with VCFS+ADHD may have a different profile of ADHD symptoms and comorbidity when compared to children with idiopathic ADHD. (J. of Att. Dis. 2007; 11(1) 64-73)

Gross Genomic Rearrangement Involving the TSC2-PKD1 Contiguous Deletion Syndrome: Characterization of the Deletion Event by Quantitative Polymerase Chain Reaction Deletion Assay

Tuberous sclerosis complex (TSC) was instrumented for identification of the gene causing autosomal dominant polycystic kidney disease type 1 (PKD1) because a patient showing both diseases gave rise to the suggestion that the TSC2 gene is located in close vicinity on chromosome 16p13. However, distinct molecular genetic characterization of such patients is sparse in the literature. A 41-year-old woman was admitted because of chylous ascites and pleural effusions. She was on hemodialysis therapy for 6 years because of end-stage renal failure from PKD. Both kidneys had been removed at ages 35 and 36 years. Histologically, both specimens also showed multiple angioleiomyolipoma. Mild, but classic, lesions of the TSC complex were present on her face and hands and in the central nervous system. The genetic defect was identified by using quantitative real-time polymerase chain reaction (qPCR), long-range PCR (LR-PCR), and sequencing. qPCR confirmed the existence of a TSC2-PKD1 contiguous gene deletion spanning the entire TSC2 and PKD1 genes. Additional analysis showed expansion of the deletion affecting the adjacent downstream-located genes RAB26 and TRAF7, as well as the great majority of CASKIN1. LR-PCR and sequencing identified flanking simple tandem repeats. A nonhomologous misalignment mechanism has driven the recombination, most likely by replication slippage between a 3-bp homology (ATG) at the breakpoint regions. Our results confirm that patients with both TSC and PKD have a genetically contiguous gene syndrome with hemizygous deletion of the TSC2 and PKD1 genes. Despite this maximal genetic defect, the typical signs of TSC, mental retardation and seizures, can be absent.

Combination of WAGR and Potocki–Shaffer contiguous deletion syndromes in a patient with an 11p11.2–p14 deletion

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki-Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki-Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented.

A contiguous deletion syndrome of X‐linked agammaglobulinemia and sensorineural deafness

Hearing loss in patients with X-linked agammaglobulinemia is often attributed to recurrent infections. However, recent genetic studies suggest a different etiology in some patients. We present three unrelated patients, 6, 9, and 14 years of age, with large deletions of the terminal portion of the Bruton tyrosine kinase (Btk) gene extending 4.2-19 kb beyond the 3' end of the gene. The DNA immediately downstream of the 3' end of Btk contains the deafness-dystonia protein gene (DDP). Mutations in this gene have recently been shown to underlie the Mohr-Tranebjaerg syndrome, which is characterized by sensorineural deafness, dystonia, and mental deficiency. Besides the immunodeficiency, our patients exhibited progressive sensorineural deafness. The clue to an associated hearing problem was delayed development of speech in one patient and post-lingual deafness noticed between the age of 3-4 years in the other two. These patients have not yet exhibited significant associated neurologic deficits.