Roger E. Stevenson

Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia

Background: Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2. Methods: Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information. Results: Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%). Conclusion: Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.

Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene.

Background: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984. Methods: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene. Results: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C). Conclusions: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.

Agenesis of the corpus callosum associated with MASA syndrome.

MASA syndrome include mental retardation, adducted thumbs, shuffling and aphasia or speech delay. MASA syndrome, X-linked hydrocephalus and X-linked spastic paraplegia have been linked to the same markers on Xq28 and perhaps represent variation in the clinical expression of the gene or manifestations of different mutant alleles. The present family includes five males in two generations with borderline to mild mental retardation (5/5), speech delay (5/5), adducted thumbs (2/5) and marked hydrocephalus (1/5). Of these males, four were evaluated by MRI or CT scan and all four were determined to have partial to complete agenesis of the corpus callosum (ACC). DNA studies confirm linkage to Xq28 probe St14 (DXS52) with a lod score of 2.86 and no recombination. It is not known if X-linked ACC is linked to the same Xq28 region.

Cognitive function in Coffin-Lowry syndrome.

Coffin–Lowry syndrome (CLS) is an X‐linked disorder associated with mental retardation, distinctive facies and hands, hypotonia, and skeletal abnormalities. The syndrome results from mutations in the RSK2 gene located in Xp22.2. Although the syndrome has been elucidated clinically, few, if any, studies have focused on the cognitive deficits of the affected males or carrier females. The subjects of the present study were selected from two African‐American families who have the same missense mutation (C340T) in RSK2. The subjects included six affected males, seven carrier females, three normal males and three non‐carrier (normal) females. Normal family members served as contrast/comparison cohorts to control for socio‐economic, sociocultural and genetic variables which would impinge on intellectual abilities. Analysis of cognitive function, as measured by the Stanford‐Binet Intelligence Scale, 4th edn, demonstrated a distinct hierarchy of abilities from normal to carrier to affected patients. The mean composite IQs of the cohorts were 90.8, 65.0 and 43.2 for normal, carrier and affected individuals, respectively. These findings lend support to the clinical concept of negative intellectual effects in carriers of certain X‐linked mental retardation conditions. X‐inactivation studies showed that carrier females had mild to significant skewing. Normal females in the family did not demonstrate skewing. The correlation coefficient between IQ and X‐inactivation status among carriers was not significant.

Nonsyndromic X‐linked mental retardation: review and mapping of MRX29 to Xp21

The gene responsible for nonsyndromic mental retardation in a family with 7 affected males has been localized to Xp21. The maximal two‐point lod score was 3.31 for tight linkage to marker DXS1202 in Xp21.3‐p22.3 with crossovers between the 3’ portion of the DMD gene (DXS 1234) proximally and locus DXS989 distally. The XLMR gene in this family has been assigned the designation MRX29. The localization overlaps with at least six other MRX entities linked to the distal short arm of the X chromosome.

Study of X-linked mental retardation (XLMR): summary of 61 families in the Miami/Greenwood Study.

The initial goal of this study was to localize as many genes as possible that lead to syndromic and nonspecific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Five large families with nonspecific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families.

Alpha-thalassemia intellectual disability

Alpha‐thalassemia intellectual disability, one of the recognizable X‐linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X‐inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha‐thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.

Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X): Alpha-thalassemia intellectual disability

Alpha‐thalassemia intellectual disability, one of the recognizable X‐linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X‐inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha‐thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.