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NGS Improves the Diagnosis of X-Linked Intellectual Disability (XLID)

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Next Generation Sequencing

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Abstract

X-linked intellectual disability (XLID) is considered to be a collection of conditions that are each caused by mutation in one of the many X-linked genes associated with either a syndromic or nonsyndromic form of intellectual disability. A significant number of XLID conditions have been described, but only approximately 50 % of the causative XLID genes have been discovered. For affected individuals from families with clear or potentially X-linked inheritance, the strategy for next-generation sequencing (NGS) can be tailored appropriately, given the ability to focus sole attention on the X chromosome rather than the entire genome. The primary goal of this chapter is to focus on the principles associated with testing known XLID genes that have been included on various targeted NGS panels. These principles can be extended to other X-linked genes that may be implicated in XLID, as well as to other genes on the X chromosome with relevant medical implications.

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Authors and Affiliations

  1. Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC, 29646, USA

    Michael J. Friez Ph.D., FACMG & Monica J. Basehore Ph.D., FACMG

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  1. Michael J. Friez Ph.D., FACMG
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  2. Monica J. Basehore Ph.D., FACMG
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Correspondence to Michael J. Friez Ph.D., FACMG .

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Editors and Affiliations

  1. , Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, Texas, USA

    Lee-Jun C. Wong

Appendix: Profiles of the Most Common XLID Syndromes

Appendix: Profiles of the Most Common XLID Syndromes

(Gene, location, and brief clinical findings in addition to intellectual disability)

1.1 Replicated with Permission from Stevenson and Schwartz [1]

1.1.1 Aarskog Syndrome

FGD1, Xp11.21

Short stature, hypertelorism, downslanting palpebral fissures, joint hyperextensibility, shawl scrotum

1.1.2 Adrenoleukodystrophy

ABCD1, Xq28

Variable and progressive vision and hearing loss, spasticity, neurological deterioration associated with demyelination of the central nervous system and adrenal insufficiency

1.1.3 Aicardi syndrome

No gene, Xp22

Agenesis of the corpus callosum, lacunar chorioretinopathy, costovertebral anomalies, seizures in females

1.1.4 Allan-Herndon Syndrome

SLC16A2, Xq13

Generalized muscle hypoplasia, childhood hypotonia, ataxia, athetosis, dysarthria, progressing to spastic paraplegia

1.1.5 ARX-Related Syndromes

(includes Partington, Proud, West, X-linked lissencephaly with ambiguous genitalia (XLAG) syndromes and nonsyndromic XLID)

ARX, Xp22.3

Partington: dysarthria, dystonia, hyperreflexia, seizures. West: infantile spasms, hypsarrhythmia. Proud: microcephaly, ACC, spasticity, seizures, ataxia, genital anomalies. XLAG: lissencephaly, seizures, genital anomalies

1.1.6 ATRX Syndrome

(includes Chudley-Lowry, Carpenter-Waziri, Holmes-Gang, and Martinez spastic paraplegia syndromes and nonsyndromic XLID)

ATRX, Xq13.3

Short stature, microcephaly, hypotonic facies with hypertelorism, small nose, open mouth and prominent lips, brachydactyly, genital anomalies, hypotonia, in some cases hemoglobin H inclusions in erythrocytes

1.1.7 Christianson Syndrome

SLC9A6, Xq26

Short stature, microcephaly, long narrow face, large ears, long straight nose, prominent mandible, general asthenia, narrow chest, long thin digits, adducted thumbs, contractures, seizures, autistic features, truncal ataxia, ophthalmoplegia, mutism, incontinence, hypoplasia of the cerebellum, and brain stem

1.1.8 Coffin-Lowry

RPS6KA3, Xp22

Short stature, distinctive facies, large soft hands, hypotonia, joint hyperextensibility, skeletal changes

1.1.9 Creatine Transporter Deficiency

SLC6A8, Xq28

Nondysmorphic, autistic, possibly progressive

1.1.10 Duchenne Muscular Dystrophy

DMD, Xp21.3

Pseudohypertrophic muscular dystrophy

1.1.11 Fragile X Syndrome

FMR1, Xq27.3

Prominent forehead, long face, recessed midface, large ears, prominent mandible, macroorchidism

1.1.12 Hunter Syndrome

IDS, Xq28

Progressive coarsening of face, thick skin, cardiac valve disease, joint stiffening, dysostosis multiplex

1.1.13 Incontinentia Pigmenti

IKBKG, Xq28

Sequence of cutaneous blistering, verrucous thickening, and irregular pigmentation. May have associated CNS, ocular abnormalities

1.1.14 Lesch-Nyhan Syndrome

HPRT, Xq26

Choreoathetosis, spasticity, seizures, self-mutilation, uric acid urinary stones

1.1.15 Lowe Syndrome

OCRL, Wq26.1

Short stature, cataracts, hypotonia, renal tubular dysfunction

1.1.16 MECP2 Duplication Syndrome

MECP2, Xq28

Hypotonia, progressing to spastic paraplegia, recurrent infections

1.1.17 Menkes Syndrome

ATP7A, Xp13.3

Growth deficiency, full cheeks, sparse kinky hair, metaphyseal changes, limited spontaneous movement, hypertonicity, seizures, hypothermia, lethargy, arterial tortuosity, death in early childhood

1.1.18 Pelizaeus-Merzbacher Disease

PLP1, Xq21.1

Nystagmus, truncal hypotonia, progressive spastic paraplegia, ataxia, dystonia

1.1.19 Renpenning Syndrome

(includes Sutherland-Haan, cerebropalatocardiac, Golabi-Ito-Hall, Porteous syndromes)

PQBP1, Xp11.3

Short stature, microcephaly, small testes. May have ocular or genital abnormalities

1.1.20 Rett Syndrome

MECP2, Xq28

XLID in female, cessation and regression of development in early childhood, truncal ataxia features, acquired microcephaly

1.1.21 X-Linked Hydrocephaly

(includes mental retardation, aphasia, shuffling gait and abducted thumbs (MASA) spectrum)

L1CAM, Xq28

Hydrocephalus, adducted thumbs, spastic paraplegia

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Friez, M.J., Basehore, M.J. (2013). NGS Improves the Diagnosis of X-Linked Intellectual Disability (XLID). In: Wong, LJ. (eds) Next Generation Sequencing. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7001-4_9

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