Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2).

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients.

Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I.

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.

A gene for an autosomal recessive lower motor neuron disease with childhood onset maps to 1p36.

OBJECTIVE: To describe the clinical features of a novel variant of autosomal recessive lower motor neuron disease (LMND) with childhood onset and to map the disease-causing gene. METHODS: The authors performed a clinical study in a large consanguineous African family. After linkage exclusion to SMN1 and SOD1 loci, they performed a genome-wide linkage analysis to map the underlying genetic defect. RESULTS: This novel variant of LMND with childhood onset and autosomal recessive mode of inheritance is characterized by a progressive symmetric and generalized involvement of the musculature. Four of the five affected patients had muscle weakness since age 3, strongly worsening during childhood and leading to generalized tetraplegia in adulthood. Genetic analyses using homozygosity mapping strategy assigned this progressive generalized LMND locus to an interval of 3.9 cM (or 1.5 megabases) on chromosome 1p36, between loci D1S508 and D1S2633 (Z(max) = 3.79 at theta = 0.00 at locus D1S253). This region encloses 27 candidate genes. CONCLUSION: Genetic mapping of a novel rare phenotype of lower motor neuron disease opens the way toward the identification of a new gene involved in motor neuron degeneration, located in the 1p36 chromosomal region.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.