PENCALC: a program for penetrance estimation in autosomal dominant diseases

PENCALC: A program for penetrance estimation in autosomal dominant diseases

Andréa R.V. Russo Horimoto; Márcio T. Onodera; Paulo A. Otto

Departamento de Genética e Biologia Evolutiva Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil

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ABSTRACT

We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows) and web versions (PenCalcWeb) of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

Key words: penetrance (rate, value), computer program, maximum likelihood estimation.

Accurate penetrance estimates are important for determining genetic disease recurrence risks in families where incompletely penetrant Mendelian disorders are segregating or for establishing genetic map locations by linkage analysis. While crude penetrance estimates can be rapidly derived by dividing the number of observed individuals expressing a disease phenotype by a rough estimate of the probable number of carriers in a given pedigree exhibiting autosomal dominant inheritance, deriving exact maximum likelihood estimates of carrier status at an individual level is time consuming and tedious. In this paper, we describe the structure and use of a computer program designed to be user friendly and assist genetic counselors and gene mappers to make accurate penetrance estimates in all sizes and complexities of autosomal dominant pedigrees, including those containing consanguineous loops and twin pairs.

The program deals with the situation of a single monogenic locus (A, a), with allele A dominant in relation to allele a. In the case of human autosomal dominant diseases, the homozygous condition AA is generally either unknown or very rare (given a low population frequency of the pathogenic allele A), so that in pedigrees with cases of autosomal dominant disease the affected individuals are almost invariably Aa heterozygotes, while normal individuals are either aa homozygotes or non-penetrant Aa heterozygotes. In this sense, the penetrance rate K is assumed to be the probability of an Aa heterozygote being affected: K = Prob(affected|Aa).

The penetrance rate estimation can be performed for polymorphic traits from familial aggregates including pairs of twins or other groups of close relatives, or, in the case of rare human diseases, through the analysis of phenotype segregation in pedigrees (a complete revision on this subject can be found in Horimoto and Otto, 2008). The algorithms are based on methods detailed by Rogatko (1986) and Horimoto (2009).

PenCalc for Windows was developed using Microsoft Visual Basic 6.0. This compressed, self-installing program can be obtained free of charge from the home page http://www.ib.usp.br/~otto/software.htm. The same page contains the access link to the PenCalcWeb Internet (www) program, developed using Active Server Pages (ASP), through the languages VBScript and Jscript. Both penetrance programs are the intellectual property of the authors, and as such, any use of or reference to the materials included in them, must contain an explicit reference to their origin. Feedback from users is welcome and will be used to improve the program and to correct unforeseen flaws.

Both programs are described in figures obtained directly in real time from screen images generated by the programs themselves.

First we describe PenCalc for Windows. To illustrate the operation of the program, we will use as example the hypothetical pedigree shown in Figure 1. At left of this figure is represented the whole pedigree and at right the filtered genealogy from which we identify the following tree structures pertinent to penetrance estimation: three affected (penetrant) individuals (II-4, III-4, and IV-1); four obligate non-penetrant individuals (I-1, II-1, II-3, and III-1); two normal individuals without offspring descending from an obligate (penetrant or non-penetrant) carrier of the gene (II-5 and II-6); and two 2-generation trees of normal individuals, one with two individuals in the second generation (II-2, III-2, and III-3), the other with three secondgeneration individuals (III-5, IV-2 to IV-4).

Options File, Data Input and Help appear in the main menu of the program's opening page. The File menu accesses options for exiting the program, for saving or printing the text file generated by the program to show the likelihood function, the estimate of K (penetrance value) and its exact 95% credibility interval. The Data Input menu program allows the writing of a data file through the File submenu option Create (Figure 2), accessing an existing data file through the File submenu option Open,orentering the data through specific program forms (Screen option, Figures 3, 4, ⁶, and ⁷). The Help menu accesses a graphic interface with the program credits (option About...) or gives information on the use of the user's Manual in pdf format.

The input of consanguineous structures is far more complicated; we shall use the example shown in Figure 5, where individuals I-1 and II-2 are assumed to be both descendents of related obligate carriers. In order to simplify not only the calculations but also the input of data, it is assumed that the dominant allele has been transmitted to the individual IV-2 of the last generation by either individual I-1 or II-2: the tree is then split into two different configurations (1 and 2), and their corresponding data entered separately.

We next describe the program PenCalcWeb. Initially, the program shows graphic interfaces for entering data, similar to those for PenCalc for Windows. Because of the flexibility of the programming language, PenCalcWeb is far more intuitive to use than PenCalc for Windows. Only the final screen with results is shown in Figure 10.

Acknowledgments

This paper was funded by a doctoral grant from CAPES to Andréa R. V. Russo Horimoto. The valuable criticism, corrections and suggestions made by our colleague Prof. Peter L. Pearson are also deeply acknowledged.

Internet Resources

Received: March 1, 2010; Accepted: May 5, 2010.

Associate Editor: Peter Pearson

License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

• Naveed M, Al-Ali MT, Murthy SK, Al-Hajali S, Al-Khaja N, Deutsch S, Bottani A, Antonarakis SE, Nath SK and Radhakrishna U (2006) Ectrodactyly with aplasia of long bones (OMIM 119100) in a large inbred Arab family with an apparent autosomal dominant inheritance and reduced penetrance: Clinical and genetic analysis. Am J Med Genet 140A:1440-1446.
• Rogatko A, Pereira CAB and Frota-Pessoa O (1986) A Bayesian method for the estimation of penetrance: application to mandibulofacial and frontonasal dysostoses. Am J Med Genet 24:231-246.
• Horimoto ARVR and Otto PA (2008) Penetrance Rate Estimation. In: Otto PA (ed) Métodos Clásicos y Modernos para el Análisis de Datos en Genética Humana. Editorial Universitaria de la Universidad Nacional de Misiones, Posadas, pp 123-150, http://www.ib.usp.br/~otto/pop_genetics.htm (February 4, 2010).
• Horimoto ARVR (2009) Estimativa do valor da taxa de penetrância em doenças autossômicas dominantes: estudo teórico de modelos e desenvolvimento de um programa computacional. PhD Thesis, Instituto de Biociências, Universidade de São Paulo, http://www.teses.usp.br (tese_HORIMOTOARVR.pdf) (February 4, 2010).

Publication Dates

• Publication in this collection
  25 June 2010
• Date of issue
  2010

History

• Received
  01 Mar 2010
• Accepted
  05 May 2010