Expanding the phenotype of RTTN variations: a new family with primary microcephaly,severe growth failure,brain malformations and dermatitis

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out‐of‐frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN‐associated diseases and ciliary dysfunction.     

Primary microcephaly,primordial dwarfism,and brachydactyly in adult cases with biallelic skipping of RTTN exon 42

Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648–5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C‐terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity.     

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. l ‐Serine is essential for neuronal survival and differentiation. Indeed, l ‐serine biosynthesis disorders affect brain development and cause severe ID. In the brain, l ‐serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of l ‐serine into neurons and the release of glia‐borne l ‐serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of l ‐serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.     

Newly recognized recessive syndrome characterized by dysmorphic features, hypogonadotropic hypogonadism, severe microcephaly, and sensorineural hearing loss maps to 3p21.3

We present a newly recognized, likely autosomal recessive, pleiotropic disorder seen in four individuals (three siblings and their nephew) from a consanguineous family of Pakistani origin. The condition is characterized by hypogonadotropic hypogonadism, severe microcephaly, sensorineural deafness, moderate learning disability, and distinctive facial dysmorphic features. Autozygosity mapping using SNP array genotyping defined a single, large autozygous region of 13.1 Mb on chromosome 3p21 common to the affected individuals. The critical region contains 227 genes and initial sequence analysis of a functional candidate gene has not identified causative mutations. © 2011 Wiley Periodicals, Inc.     

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.     

Mild growth retardation and developmental delay,microcephaly, and a distinctive facial appearance

We describe a brother and sister from one family and a girl from a second, unrelated family; they have a syndrome of pre- and postnatal growth deficiency, developmental delay, a friendly personality, microcephaly, and a distinctive facial appearance marked by thick eyebrows, full cheeks, and a short nose with the columella inserted below the nasal alae. We think this is a new syndrome probably inherited as an autosomal recessive trait. © 1994 Wiley-Liss, Inc.     

FAM160B1 deficit associated with microcephaly,severe intellectual disability,ataxia, behavioral abnormalities and speech problems

Intellectual disability (ID) varies in severity and is often associated with a variety of other clinical features. In consanguineous populations ID is usually inherited in an autosomal recessive fashion. Many genes are known for the condition, but many more are yet to be identified. By linkage analysis and exome sequencing we identified homozygous early truncating variant c.115G > T (p.Glu39*) in FAM160B1 in a 38-year-old woman with severe ID, microcephaly, behavioral abnormalities, speech problems, mild ataxia and mild facial dysmorphism. Recently homozygous missense c.248 T > C (p.Leu83Pro) was reported to underlie the ID syndrome in a 7-year-old boy and his two younger siblings. Some findings for those siblings overlap with those for our patient, but our patient does not have cutis laxa. Our findings confirm FAM160B1, with unknown function, as a syndromic ID gene and indicate that FAM160B1 is not essential for survival but is vital for proper functioning of the nervous system, delineate the FAM160B1-related ID, and describe the disease in a much older age.     

Amish lethal microcephaly: A new metabolic disorder with severe congenital microcephaly and 2‐ketoglutaric aciduria

A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2‐ketoglutaric aciduria has been found among the Old‐Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2‐ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20‐week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2‐ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2‐ketoglutarate transporter. © 2002 Wiley‐Liss, Inc.     

Syndrome of microcephaly,microphthalmia, cataracts,and intracranial calcification

We present two sisters with microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and intracranial calcification. No evidence of intrauterine infection was found. There have been previous reports of microcephaly, intracranial calcification, and an intrauterine infection-like autosomal recessive condition, but the sibs in this report appear to represent a more severe form of such a condition or a previously undescribed entity. Am. J. Med. Genet. 84:330–333, 1999. © 1999 Wiley-Liss, Inc.     

Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures

Microdeletion of chromosome 2q23.1 results in a novel syndrome previously reported in five individuals. Many of the del(2)(q23.1) cases were thought to have other syndromes such as Angelman, Prader–Willi, or Smith–Magenis because of certain overlapping clinical features. We report two new cases of the 2q23.1 microdeletion syndrome, describe the syndrome phenotype, define the minimal critical region, and analyze the expression of critical region genes toward identification of the causative gene(s) for the disorder. Individuals with del(2)(q23.1) have severe developmental and cognitive delays, minimal speech, seizures, microcephaly, mild craniofacial dysmorphism, behavioral disorders, and short stature. The deletions encompassing 2q23.1 range from >4 Mb to <200 kb, as identified by oligonucleotide and BAC whole-genome array comparative hybridization. The minimal critical region includes a single gene, MBD5, deleted in all cases, whereas all but one case also include deletion of EPC2. Quantitative real-time PCR of patient lymphoblasts/lymphocytes showed an ∼50% reduced expression of MBD5 and EPC2 compared with controls. With similar phenotypes among the 2q23.1 deletion patients, the idea of one or more common genes causing the pathological defect seen in these patients becomes evident. As all five previous cases and the two cases in this report share one common gene, MBD5, we strongly suspect that haploinsufficiency of MBD5 causes most of the features observed in this syndrome.     

Apparently new osteodysplastic and primordial short stature with severe microdontia,opalescent teeth,and rootless molars in two siblings

A Thai man and his sister affected with a newly recognized syndrome of proportionate primordial short stature are reported. The patients had severe intrauterine and postnatal growth retardation, prominent nose and nasal bridge, small pinnae, large sella turcica, areas of hypo‐ and hyperpigmentation of skin, dry and thin scalp hair, and long and straight clavicles. Ivory epiphyses and cone‐shaped epiphyses of the hands were found when they were young, but most of them disappeared as they grew up. Scaphoid and trapezium had angular appearance. The second toes were unusually long. Distal symphalangism of toes and barchymesophalangy of fingers were noted. The findings that appear to distinguish this syndrome from the previously reported syndromes are long second toes, opalescent and rootless teeth, severe microdontia, severely hypoplastic alveolar process, and unerupted tooth. The mode of inheritance is suspected to be autosomal recessive. © 2002 Wiley‐Liss, Inc.     

Distinctive syndrome of short stature,craniosynostosis, skeletal changes,and malformed ears

We report on 2 unrelated boys with a distinctive facial appearance of microtia, atretic external auditory meati, small mandible, and microstomia, who also have a skeletal dysplasia, microcephaly, and joint contractures. The skeletal abnormalities, short stature, and microcephaly led to an initial diagnosis of osteodysplastic primordial dwarfism; however, the birth weight of one of the children is not low enough to firmly establish this diagnosis. The similarities were detected by the matching program of the London Dysmorphology Data-base.